Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26]O)[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7].[CH:33]([N:36](C(C)C)[CH2:37]C)(C)C.CNC>C1COCC1>[CH2:6]([S:8]([C:11]1[CH:12]=[C:13]([C:17]2[CH:25]=[C:24]([CH2:26][N:36]([CH3:37])[CH3:33])[CH:23]=[C:22]3[C:18]=2[C:19]2[CH:31]=[C:30]([CH3:32])[CH:29]=[N:28][C:20]=2[NH:21]3)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Methanesulfonyl chloride (18 μL, 0.24 mmol) was added to a solution of Compound 133 (46 mg, 0.12 mmol) and diisopropylethylamine (43 μL, 0.25 mmol) in THF (1 mL) at 0° C. After stirring for 3 h, dimethylamine (2M, 1 mL, 2 mmol) was added, and the reaction stirred for 16 h. The solution was concentrated in vacuo and purified by prep-HPLC to give 32 mg (65%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CD3OD) δ 8.36 (br s, 1H), 8.22 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.05 (d, 1H, J=7.6 Hz), 7.88-7.94 (m, 2H), 7.85 (s, 1H), 7.44 (s, 1H), 4.57 (s, 2H), 3.33 (q, 2H, J=7.2 Hz), 2.94 (s, 6H), 2.39 (s, 3H), 1.30 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C23H25N3O2S, 408; found 408.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCCCC)=O.Br.[NH2:27][CH2:28][C:29]([N:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1([CH3:38])[CH3:37])=[O:30]>ClCCl>[CH3:37][C:32]1([CH3:38])[NH:33][C:34](=[O:36])[CH2:35][N:31]1[C:29](=[O:30])[CH2:28][NH:27][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC1=O
Reactant: CC1(C)NC(=O)CN1C(=O)CN
Agent: Br
Agent: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)NC(=O)CN1C(=O)CNC(=O)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An ice cold solution of 2-oxo-1-pyrrolidineacetic acid (1.03 g) and triethylamine (1.01 ml) in dichloromethane (20 ml) was treated dropwise with butyl chloroformate (0.92 ml). After stirring at 0° C. for 30 minutes a suspension of 1-(2-aminoacetyl)-2,2-dimethyl-4-imidazolidinone hydrobromide (1.82 g) and triethylamine (1.01 ml) in dichloromethane (20 ml) was added, and the temperature was gradually raised to room temperature. After stirring at room temperature for 1 day the suspension was evaporated under reduced pressure. The residue was chromatographed on a silica/gel column eluting with methanol/dichloromethane 1:1. The selected fractions were collected and evaporated, the residue was washed with ethyl acetate and crystallized from ethanol to give the title compound as a white solid, m.p. 229°-231° C.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:32]=[CH:31][C:26]([CH:27]=[CH:28][CH:29]=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[Cl:8][C:6]1[CH:7]=[C:2]([CH:29](/[CH:28]=[CH:27]/[C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:32][CH:31]=2)[OH:30])[C:3]([O:9][CH3:10])=[N:4][CH:5]=1
Reactant: O=CC=Cc1ccc(Cl)cc1
Reactant: COc1ncc(Cl)cc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ncc(Cl)cc1C(O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4.0 g of 3-bromo-5-chloro-2-methoxypyridine in 75 ml of anhydrous ether was cooled to -70° C. under nitrogen. The resulting slurry was stirred rapidly and there was added 12.0 ml of 1.65M n-butyllithium/hexane dropwise over a period of about 5 minutes while keeping the temperature below -70° C. The reaction mixture became homogeneous and, after 15 minutes, a solution of 3.0 g of 4-chlorocinnamaldehyde in 35 ml of ether was added dropwise while keeping the temperature below -60° C. The cold mixture was then poured into aqueous saturated sodium bicarbonate solution and the resulting mixture was extracted with ether. The ether layer was washed with aqueous saturated sodium chloride solution, dried over potassium carbonate and concentrated under reduced pressure to give a white solid. This solid was recrystallized from a mixture of ethyl acetate/hexane to give (E)-5-chloro-α-[2-(4-chlorophenyl)ethenyl]-2-methoxy-3-pyridinemethanol as white needles melting at about 135°-139.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:16]1[CH:21]=[CH:20][C:19]([C:7]([C:3]2[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2cccnc2C(=O)O)cc1

Procedure:
Employing 2,3-pyridinedicarboxylic anhydride (10.0 g), toluene (125 ml) and aluminum chloride (15.0 g), substantially the same reaction and process as in Reference Example 1 Process 1 and Step 1 were conducted to give 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid as colorless crystals (7.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([N:39]1C2=C3C(=CC=[C:42]2[CH:41]=[N:40]1)C(=O)C(I)=C(C1C=CC=CC=1)O3)C>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:40]([CH2:41][CH3:42])[N:39]=[CH:37][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: CCn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Product: CCn1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 84 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 1-ethyl-7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a colourless solid (44.4 mg, 84%). LCMS (Method H): RT=4.50 min, [M+H]+=536.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])(=[O:16])=[O:15].[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>CN(C=O)C>[CH3:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)(=[O:15])=[O:16]
Reactant: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Reactant: BrCCOC1CCCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(CCOC1CCCCO1)S(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Reaction time: 20 h

Procedure:
To a suspension of N,N-dimethyl 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzamide hydrochloride (347 mg, 0.91 mmol) in DMF (5 ml) under N2 was added 50% NaH (87 mg, 1.82 mmol). After stirring at 20°-25° for 15 minutes until all of the NaH had reacted, a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran in DMF (2 ml) was added. The solution was stirred at 20°-25° under N2 for 20 hours and then concentrated under reduced pressure to remove most of the DMF. The residue was partitioned between EtOAc and a saturated aqueous solution of NaCl. After drying (Na2SO4) the EtOAc extract, filtering and concentrating, the residue was chromatographed over silica gel. Elution with 7% MeoH-93% CHCl3 gave 100 mg of product.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH3:7][C:8]1[NH:9][CH:10]=[C:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[PH2](O)=O>I.O>[CH3:7][C:8]1[NH:9][C:10]([CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[C:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CCC(=O)CC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: I
Agent: O=[PH2]O
Solvent: O
Product: CCC(CC)c1[nH]c(C)c(C(C)=O)c1C
Reaction time: 4 h

Procedure:
3-Pentanone (0.85 ml) was added to a solution of 548 mg of 2,4-dimethyl-3-acetyl-pyrrole, in 10 ml of aq. hydriodic acid, 10 ml of acetic anydride and 2 ml of hypophosphorous acid. The solution was stirred for 13/4 hours then poured into 200 ml of water to precipitate the product as tiny nearly colourless prisms (651 mg, 79%), m.p. about 186°-189° C. For analysis it was recrystallized from ethanol as colourless plates, m.p. 188.5° C. after a solid phase change at 135°. Anal. Calc. for C13H21NO: C, 75.31; H, 10.21; N, 6.76. Found: C, 75.13; H, 10.04; N, 6.78.
Reaction SMILES: N1(CCCC(C2C=CC3OC4C(=CC(C(=O)CCCN5CCCCC5)=CC=4)CC=3C=2)=[O:11])CCCCC1.[N:37]1([CH2:43][CH2:44][CH2:45][CH2:46][C:47]([C:49]2[CH:62]=[CH:61][C:60]3[O:59][C:58]4[C:53](=[CH:54][C:55]([C:63](=[O:74])[CH2:64][CH2:65][CH2:66][CH2:67][N:68]5[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]5)=[CH:56][CH:57]=4)[CH2:52][C:51]=3[CH:50]=2)=[O:48])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[N:37]1([CH2:43][CH2:44][CH2:45][CH2:46][C:47]([C:49]2[CH:62]=[CH:61][C:60]3[O:59][C:58]4[C:53](=[CH:54][C:55]([C:63](=[O:74])[CH2:64][CH2:65][CH2:66][CH2:67][N:68]5[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]5)=[CH:56][CH:57]=4)[C:52](=[O:11])[C:51]=3[CH:50]=2)=[O:48])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCCCC3)ccc1O2
Reactant: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1O2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCCCN1CCCCC1)c1ccc2oc3ccc(C(=O)CCCCN4CCCCC4)cc3c(=O)c2c1

Procedure:
Following the procedure of Example 42, only substituting for 2,7-bis(4-piperidinobutyryl)xanthene, 25.8 g (0.05 mole) 2,7-bis(5-piperidinovaleryl)xanthene and using 600 ml of glacial acetic acid and 19.7 g (0.066 mole) sodium dichromate, the solid obtained is recrystallized from a benzene-heptane mixture to give the title compound, M.P. 109°-110° C.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br>>[F:4][C:5]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:2][NH2:3]
Reactant: Fc1cccc(CBr)c1F
Reactant: NN
Solvent: O
Product: NNCc1cccc(F)c1F

Procedure:
Preparation takes place in analogy to that described in Example 1 A from 2.74 g (54.75 mmol) of hydrazine hydrate and 3.02 g (14.60 mmol) of 2,3-difluorobenzyl bromide. For work up, the residue is purified by flash chromatography (mobile phase: dichloromethane:methanol 30:1–10:1).
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(C([Cl:21])=O)=O>C(Cl)Cl>[C:4]1([CH2:3][CH2:2][C:1]([Cl:21])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
A 200 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with hydrocinnamic acid (5.00 g, 33.3 mmol), DMF (0.1 mL), and CH2Cl2 (30 mL). To the resultant solution was added (COCl)2 (2M in CH2Cl2, 20.0 mL, 40.0 mmol) over 30 min. The mixture stirred overnight at rt, and then was concentrated in vacuo to give 5.9 g of 74 as a yellow oil (100%). HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with a retention time of 5.3 min.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.B(O)(O)O.C1(C)C(C)=CC=CC=1>O>[O:9]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)CCCCCC(=O)[O-]
Agent: OB(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)CCCCCc1nc2ccccc2o1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of monoethyl heptanedioate (9.41 g), o-aminophenol (5.46 g), boric acid (3.09 g), and xylene (100 ml) was refluxed with water being azeotropically removed for 16 hours. After cooling to room temperature, the insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to provide ethyl 6-(benzoxazol-2-yl)hexanoate (10.1 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C1CCN2C(=NCCC2)CC1>C(O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2nc3ccccc3[nH]2)cc1
Yield: 15.3 %

Procedure:
2-Chlorobenzimidazole (0.033 moles, 5.0 g), 4-nitrothiophenol (0.033 moles, 4.14 g), and DBU (0.033 moles, 5.0 g) in 200 ml ethanol were heated at 55° C. for 3 hr. The reaction was concentrated, ethyl acetate added, washed with water, dried over sodium sulfate and the solvent removed. The solid was slurred in hexane to yield 2-(4-nitrophenylthio)benzimidazole 1.37 g, 15%. Mass Spec (FD) 271. Calculated for C13H8N3O2S: C, 57.55; H, 3.34; N, 15.49. Found: C, 57.50; H, 5.54; N, 15.23.
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10]CC)=O)[CH:4]=[O:5])=[CH2:2].[CH2:13]([NH2:16])[CH:14]=[CH2:15].C[O-].[Na+]>CO>[CH2:13]([NH:16][C:8](=[O:10])[CH2:7][CH2:6][N:3]([CH:1]=[CH2:2])[CH:4]=[O:5])[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: C=CN(C=O)CCC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCNC(=O)CCN(C=C)C=O
Temperature: 90 °C

Procedure:
A 100mL stainless steel high pressure reactor was charged with 17.1 grams (0.1 mol) of ethyl 3-(N-vinylformamido)propionate, 5.7 grams (0.1 mol) of allylamine and 0.15 gram of 25% sodium methoxide in methanol solution. The mixture was heated at 90° C. for 3 hours. Subsequent NMR analysis of the reaction mixture showed no conversion of the starting materials.
Reaction SMILES: [C:1]([C:5]1[CH:52]=[CH:51][C:8]2[NH:9][C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([N:17]([CH2:19][C@@H:20]4[C@H:24]5[O:25]C(C)(C)[O:27][C@H:23]5[C@H:22]([N:30]5[C:34]6[N:35]=[CH:36][N:37]=[C:38]([NH:39]CC7C=CC(OC)=CC=7OC)[C:33]=6[CH:32]=[CH:31]5)[O:21]4)[CH3:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O.O>[NH2:39][C:38]1[C:33]2[CH:32]=[CH:31][N:30]([C@H:22]3[C@H:23]([OH:27])[C@H:24]([OH:25])[C@@H:20]([CH2:19][N:17]([CH:15]4[CH2:14][CH:13]([CH2:12][C:10]5[NH:9][C:8]6[CH:51]=[CH:52][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=6[N:11]=5)[CH2:16]4)[CH3:18])[O:21]3)[C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(Cc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1O[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
7-((3aR,4R,6R,6aR)-6-(((3-((5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)methyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (170 mg, 0.24 mmol) was dissolved in a mixture of trifluoroacetic acid (5.0 mL) and water (0.5 mL) which had been precooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, and warmed to room temperature. After 5 h at room temperature, the now very pink reaction mixture was concentrated. The residue was taken up in 10 mL MeOH and concentrated. This procedure was repeated twice and the residue placed on high vac for 1 h. The material was taken up in 7 mL MeOH and was treated with 130 mg K2CO3 and five drops of water. The mixture was allowed to stir for 1 hr, during which time the solution was found to be basic. The mixture was filtered through a fine frit, the solids were washed with 10 mL MeOH and the filtrate was concentrated to yield a nearly colorless solid. The crude material was purified by flash chromatography (30 g silica gel; 12% 7N NH3 in CH3OH/CH2Cl2) to yield Compound 6 (81 mg, 65%) as a colorless glass/stiff foam: MS (ESI+) for C28H37N7O3 m/z 520.4 (M+H)+; MS (ESI−) for C28H37N7O3 m/z 518.5 (M−H)−; HPLC purity >95% (ret. time, 2.51 min); 1H NMR (400 MHz, d4-MeOH) δH ppm 8.08 (s, 1H), 7.48 (br. s., 1H), 7.39 (d, J=8.50 Hz, 1H), 7.29 (dd, J=8.40, 4.87 Hz, 1H), 6.63 (m, 1H), 6.12 (d, J=4.15 Hz, 1H), 4.40 (m, 1H), 4.09 (m, 2H), 3.15 (m, 0.5H), 3.02 (d, J=8.09 Hz, 1H), 2.92 (d, J=7.26 Hz, 1H), 2.84 (m, 0.5H), 2.65 (m, 2H), 2.43 (m, 1H), 2.29 (m, 1H), 2.20 (d, J=5.80 Hz, 3H), 2.13 (m, 1H), 1.99 (br. s., 1H), 1.67 (m, 1H), 1.37 (d, J=3.94 Hz, 9H), 1.30 (dd, J=13.99, 4.66 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[Mg].II.[N:13]([P:18](Cl)Cl)([CH2:16][CH3:17])[CH2:14][CH3:15]>CCOCC.C1COCC1>[CH2:14]([N:13]([P:18]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])[CH2:16][CH3:17])[CH3:15]
Reactant: CCN(CC)P(Cl)Cl
Reactant: Cc1ccc(Br)c(C)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CC)P(c1ccc(C)cc1C)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.92 ml (21.61 mmol) of 4-bromo-1,3-dimethylbenzene in 3 ml of Et2O were added at 0° C. to a suspension of 0.5 g (20.56 mmol) of magnesium turnings in 7 ml of THF and 7 ml of Et2O and also a crystal of iodine. The mixture was heated to room temperature, stirred further overnight and slowly added dropwise at 0° C. to a solution of 1.5 ml (10.31 mmol) of Et2NPCl2 in 8 ml of THF. The mixture was heated to 5–10° C., stirred for a further 2 hours and the solvent was subsequently removed under reduced pressure. After adding 60 ml of hexane, the mixture was filtered through Celite under argon and the solvent was subsequently removed under reduced pressure. Yield: 1.37 g (59% of theory). 1H NMR (400 MHz, CDCl3) δ, 6.9 (m, 6H), 3.03 (m, 4H, CH2), 2.20 (s, 12H, CH3), 0.81 (t, 3J=7.0 Hz, 6H, CH3) 31P NMR (161.9 MHz, CDCl3) δ, 47.8.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:6]=1.N.[OH:20]O.O>CN1C(=O)CCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[C:11]([CH:10]=[C:9]([C:15]([F:18])([F:16])[F:17])[CH:8]=2)[C:12]([NH2:13])=[O:20])[CH:6]=1
Reactant: Cc1cn(-c2cc(C#N)cc(C(F)(F)F)c2)cn1
Reactant: OO
Agent: N
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2cc(C(N)=O)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A solution of 5-(4-methyl-imidazol-1-yl)-3-trifluoromethyl-benzonitril (3.5 g, 13.93 mmol) in NMP (28 mL) is treated with aqueous ammonia (9.8 mL, 25%) and aqueous hydrogen peroxide (3.5 mL, 30%). The resulting mixture is stirred for 1 hour at 20-25° C. and then poured into chilled water (420 mL). The resulting suspension is filtered and the filter cake is washed with water (50 mL), and dried in vacuo at 50° C. to give 3.2 g of the title compound (XXIII) (85.4%) as white crystals (98% area by HPLC).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:12][CH:13]=2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)Cl>[Br:27][C:13]1[O:12][C:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[N:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ccc(-c2coc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CSc1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc2Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
tert-butyl 4-{4-[4-(methylsulfanyl)phenyl]-1,3-oxazol-2-yl}piperidine-1-carboxylate (585 mg, 1.56 mmol) was dissolved in dichloromethane (15.6 mL) under argon atmosphere. N-bromosuccinimide (306 mg, 1.72 mmol) was added portionwise as a solid to the stifling solution. The resulting solution stirred at 25° C. for 6 hours. The solution was then diluted with chloroform and washed with aqueous sodium bisulfite. The organics were dried over sodium sulfate and concentrated in vacuo to yield 680 mg of the desired product as yellow oil. LCMS (M+1)=453.40
Reaction SMILES: Cl[C:2]1[C:3]([F:15])=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[F:10][C:5]1[C:6]([F:9])=[C:7]([F:8])[CH:2]=[C:3]([F:15])[C:4]=1[C:11]([F:14])([F:13])[F:12]
Reactant: [H][H]
Reactant: Fc1c(F)c(Cl)c(F)c(C(F)(F)F)c1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cc(F)c(C(F)(F)F)c(F)c1F
Yield: 96.3 %

Procedure:
252.5 g (1 mol) of 3-chloro-2,4,5,6-tetrafluorobenzotrifluoride (cf., for example, Zh. obshch. Khim., 37, 1686-1687 [1967]) and 86 g (1.05 mol) of sodium acetate in 1000 ml of glacial acetic acid are hydrogenated in the presence of 10 g of palladium-on-activated charcoal (5% strength) at a hydrogen pressure of 30 to 50 bar and 120° C. to constant pressure. For working-up, the catalyst is removed from the cold reaction mixture by filtration, and the residue is distilled. 210 g (96% of theory) of 2,3,4,6-tetrafluorobenzotrifluoride of boiling point 105°-106° C. and of refraction index nD20 =1.3770 are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 2 h

Procedure:
15 g (43.4 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 1.85 g (46.3 mmol) of sodium hydroxide are treated with 60 ml of ethanol and 10 ml of water, then heated to boiling under reflux for 45 minutes, the ethanol is subsequently distilled off in vacuo, the residue is treated with 46.5 ml of 1 N hydrochloric acid and left to stand in an ice-bath for 2 hours. The precipitated material is filtered off under suction, washed with water and dried to constant weight. There is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid which has a decomposition point of 265°.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH2:30])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]>C(Cl)Cl>[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH:30][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]
Reactant: COC(=O)c1cc2cccc(N)c2s1
Reactant: O=C(O)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2cccc(NC(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
Nicotinic acid (401 mg, 3.26 mmol) was suspended in 20 mL CH2Cl2 and Et3N (330 mg, 3.26 mmol, 245 uL) was added to give a colorless solution. BopCl (829 mg, 3.26 mmol) was added and the reaction was stirred at room temperature for about 15 min, then a solution of 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (450 mg, 2.17 mmol) in 2 mL CH2Cl2 was added. The yellow solution was stirred at room temperature for 12 h. After this time, room temperature, the solvent was removed from the reaction and the residue was partitioned between EtOAc (100 mL) and water (75 mL). The layers were separated and the organic portion was washed with water (2×75 mL), brine (75 mL), dried (MgSO4), filtered and the solvent was removed in vacuo to afford 7-[(pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a yellow solid (460 mg, 45%).