Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[C:5]1([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=3[N:10]=[CH:9]2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2c(ncn2-c2ccccc2)[nH]1
Reaction time: 16 h

Procedure:
A suspension of ethyl 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (EXAMPLE 1) (50 mg) and 10% Pd—C (100 mg) in ethanol (10 mL) and ethyl acetate (10 mL), was hydrogenated at atmospheric pressure for 16 h. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to yield ethyl 1-phenyl-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate EXAMPLE 2. LC-MS (ES+): m/z 256 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=1.46 (t, J=7.1 Hz, 3H), 4.42 (q, J=7.1 Hz, 2H), 7.22 (d, J=1.0 Hz, 1H), 7.48 (m, 1H), 7.69 (m, 2H), 7.94 (m, 2H), 8.73 (s, 1H), 12.28 (br s, 1H, NH).
Reaction SMILES: Br[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[F:11]
Reactant: N#Cc1cccc(F)c1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1cccc(F)c1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-3-fluorobenzonitrile (2.50 g, 12.5 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 51 to give 6,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (400 MHz, CDCl3) 7.40-7.44 (1H, m), 7.47-7.52 (1H, m), 7.59-7.67 (2H, m), 8.37-8.44 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=2)=[NH:9])=[N:6][CH:7]=1.Cl.[CH3:22][C:23]1[N:24]=[C:25](N)[S:26][C:27]=1[CH3:28]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([F:20])[CH:11]=2)=[N:9]/[C:25]2[S:26][C:27]([CH3:28])=[C:23]([CH3:22])[N:24]=2)=[N:6][CH:7]=1
Reactant: N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: Cc1nc(N)sc1C
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1nc(/N=C(\c2cc(F)cc(C(F)(F)F)c2)c2ccc(Cl)cn2)sc1C
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of (5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methanimine (1.7 g, 5.6 mmol) and 4,5-dimethylthiazol-2-amine HCl salt (900 mg, 5 mmol) in o-xylene (10 mL) was heated at 150° C. for 18 h, then allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue purified by ISCO chromatography (80 g column) using hexanes/EtOAc (0-40%) over 25 min to give (E)-N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-4,5-dimethylthiazol-2-amine as a beige solid (910 mg, 44% yield). LCMS RT=4.00 min [M+H] 413.87 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]2[CH2:23][NH:22][CH2:21][CH2:20]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:22]2[CH2:23][CH:19]([NH:18][S:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)(=[O:17])=[O:16])[CH2:20][CH2:21]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(NC1CCNC1)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NC1CCN(S(=O)(=O)c2ccc(Cl)cc2)C1)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 28.9 %

Procedure:
To a solution of (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine trifluoroacetate (7.85 g) in dichloromethane (80 ml) were added triethylamine (8.98 ml) and 4-chlorobenzenesulfonyl chloride (3.40 g) under an ice bath cooling and the mixture was stirred at the same temperature for 1.5 hours. The solution was washed successively with diluted hydrochloric acid and water and the organic phase was extracted with 1N aqueous sodium hydroxide. The aqueous phase was washed with ethyl acetate and adjusted to pH 3 with 3N hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the organic phase was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with chloroform as an eluent to give (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino) pyrrolidine (2.03 g) as a pale yellow crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12][N:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.N([O-])=O.[Na+].[CH3:17][C:18]1[C:23](N)=[CH:22][C:21]([N+]([O-])=O)=CN=1.[OH-:28].[Na+]>O.C(O)(=O)C.C(OCC)(=O)C>[O:28]1[CH2:21][CH2:22][CH2:23][CH2:18][CH:17]1[N:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([NH2:1])[CH:5]=2)[CH:10]=[N:11]1
Reactant: Cc1ncc([N+](=O)[O-])cc1N
Reactant: [OH-]
Reactant: O=[N+]([O-])c1cnc2cn[nH]c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cnc2cnn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Nitro-1H-pyrazolo[4,3-b]pyridine. A solution of sodium nitrite (2.163 g, 31.3 mmol) in water (20 mL) was added to a stirred solution of 2-methyl-5-nitropyridin-3-amine (4 g, 26.1 mmol) in acetic acid (70 mL). The resulting orange solution was stirred at room temperature for 16 h. The reaction was cooled to 0° C. and the reaction mixture was brought to pH=7 via addition of aqueous sodium hydroxide (6 M). Water and ethyl acetate were added. The resulting mixture was shaken in a reparatory funnel and the layers were separated. The organics were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was triturated with diethyl ether. Solids were collected by vacuum filtration, washed with diethyl ether, and dried under high vacuum to give the desired product, as a dark orange solid (2.3 g, 14.01 mmol, 53.7% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.29 (d, J=2.34 Hz, 1H), 8.91 (br s, 1H), 8.59 (br s, 1H). MS (ESI) m/z 165.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:25][C:26]1[C:34]2[C:33](Cl)=[N:32][CH:31]=[N:30][C:29]=2[NH:28][CH:27]=1.C(N(CC)CC)C>C(O)(C)C>[Br:25][C:26]1[C:34]2[C:33]([N:19]3[CH2:18][CH2:17][C:16]([CH3:22])([C:14]([NH:13][C:9]4[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=5)[CH:8]=4)=[O:15])[CH2:21][CH2:20]3)=[N:32][CH:31]=[N:30][C:29]=2[NH:28][CH:27]=1
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]cc(Br)c23)CC1
Temperature: 100 °C

Procedure:
To a solution of N-(3-(4-fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from example 1, step B, (36 mg, 0.1 mmol) in isopropanol (1 mL), was added to 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine from step A (24 mg, 0.1 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was heated at 100° C. for 10 minutes under microwave condition, and then concentrated under vacuum. The product was isolated by prep HPLC to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][C:14]([O:19][CH3:20])([CH2:16][O:17][CH3:18])[CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:21]([NH2:23])=O.C([O-])=O.[NH4+]>>[CH3:20][O:19][C:14]1([CH2:16][O:17][CH3:18])[CH2:13][CH2:12][C:5]2[C:6]3[C:7]([OH:8])=[N:23][CH:21]=[N:1][C:2]=3[S:3][C:4]=2[CH2:15]1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1CCC(COC)(OC)C2
Agent: O=C[O-]
Agent: [NH4+]
Product: COCC1(OC)CCc2c(sc3ncnc(O)c23)C1
Yield: 84 %

Procedure:
A mixture comprising 21.46 g (71.7 mmol) (RS)-ethyl 2-amino-6-methoxy-6-(methoxymethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (prepared according to intermediate example 16c), 114 mL methanamide and 7.23 g ammonium formate was stirred at 150° C. overnight. The reaction mixture was cooled in an ice bath, the precipitate was filtered off, washed with water and ethanol and dried to give 16.95 g (84%) of the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:17])([F:16])[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1.CCOCC>[F:4][C:5]([F:17])([F:16])[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:2][NH2:3])=[O:12])=[CH:9][CH:8]=1
Reactant: NN
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NNC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To an ice-cooled solution of hydrazine hydrate (16 mL, 25% (w/w), 125 mmol) in THF (100 mL) was added a solution of 4-trifluoromethoxybenzoyl chloride (4.3 g, 19.2 mmol) in THF (50 mL) over 30 min. The solution was stirred for a further 30 min and then diluted with ether (200 mL). The turbid organic solution was then washed with water (3×200 mL) and brine (200 mL). After drying (Na2SO4), solvent was removed by rotary evaporation. The solid residue was dissolved in ethanol/water (1:1, 200 mL), insoluble material was filtered off, and the filtrate taken to dryness to leave 3.63 g (86%) of pure 4-trifluoromethoxybenzoic acid hydrazide.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@@H:10]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](C(OC(C)(C)C)=O)=[CH:32][CH:31]=2)=[O:28])[C:9]1=[O:43])=[O:6])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)[C:46]([OH:48])=[O:47]>C(Cl)Cl>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][C@@H:10]([NH:26][C:27](=[O:28])[NH:29][C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:46]([OH:48])=[O:47])[C:9]1=[O:43])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)[C@H](NC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)CN2C1CCCCC1
Solvent: ClCCl
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)[C@H](NC(=O)Nc1cccc(C(=O)O)c1)CN2C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(4-tert-butoxycarbonylphenyl)urea (100 mg) was dissolved in methylene chloride (1 ml), trifluoroacetic acid (1 ml) was added, the mixture was stirred at room temperature for 30 minutes. After the solvent was evaporated, isopropyl ether was added to the residue, powder so precipitated was collected by filtration, to thereby obtain 50 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8]([NH2:17])([C:14]([OH:16])=[O:15])[CH2:9]2)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C(#N)C.O>[C:25]([CH:9]1[C:10]2[C:5](=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][C:8]1([NH2:17])[C:14]([OH:16])=[O:15])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41]
Reactant: CC(C)c1cccc2c1CCC(N)(C(=O)O)C2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
A mixture of racemic 5-isopropyl-2-aminotetraline-2-carboxylic acid (250 mg, 1.07 mmole), triethylamine (1.2 ml, 8.61 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 2.70 g, 8.00 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-isopropyl-2-aminotetraline-2-carboxylic acid (208 mg, 43% yield) as an off-white foam. HRMS (FAB): C29H30NO4 (M+H) calc. 456.2175; observed: 456.2184.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4]O.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[N+]([C:24]1[NH:25][CH:26]=[C:27]([N+]([O-])=O)[N:28]=1)([O-])=O.[SiH3]OO.O1C=CCCC1>>[N:28]1[C:27]2=[CH:4][CH:2]=[CH:1][O:3][C:26]2=[N:25][CH:24]=1
Reactant: OCC1CO1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: C1=COCCC1
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: OO[SiH3]
Product: c1coc2ncnc-2c1

Procedure:
According to this process, the compound (B) obtained starting from glycidol and t-butyldimethylsilyl ether is reacted with 2,4-dinitroimidazole, and after protecting the hydroxy group of the resulted siloxy alcohol (C) with dihydropyran, the tetrahydropyranyl (THP) ether compound (D) is subjected to desilylation and cyclization to form imidazopyran skeleton (E) and then, the imidazopyran derivative (F) is obtained by removal of THP group.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:58])[CH2:56][NH:55][CH2:54][C@H:53]1[OH:57]>>[C:28]([C:32]1[N:33]=[C:34]([N:55]2[CH2:56][C:52]([F:58])([F:51])[C@H:53]([OH:57])[CH2:54]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O[C@@H]1CNCC1(F)F
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2C[C@@H](O)C(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-4,4-difluoropyrrolidin-3-ol hydrochloride and isolated as white solid. MS (m/e): 423.3 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH3:10][N+:11]([CH3:13])=[CH2:12].[I-:14]>C(O)(=O)C>[IH:14].[CH3:10][N:11]([CH2:13][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:12]
Reactant: c1cnc2[nH]ccc2c1
Reactant: C=[N+](C)C
Reactant: [I-]
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2ncccc12
Product: I
Temperature: 65 °C

Procedure:
7-Azaindole (5.05 g, 43 mmol) and Eschenmoser's salt (N,N-dimethylmethyleneammonium iodide; 8.48 g, 45 mmol) are combined in 100 ml of glacial acetic acid. After heating at 65° C. for 1 hour, the reaction mixture is concentrated in vacuo. The resulting solid is triturated with ethyl acetate, filtered and dried in vacuo to give 3-dimethylaminomethyl-1H-7-azaindole hydroiodide in quantitative yield.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10]C(C1C=NC=CC=1)=O)=[O:6].C[I:22].[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[I-:22].[F:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][CH2:8][CH2:9][O:10][C:27]([CH:26]1[CH2+:25]=[CH:24][CH:2]=[CH:3][N:4]1[CH3:5])=[O:23])=[O:6]
Reactant: C1CCOC1
Reactant: CI
Reactant: O=NN(CCF)C(=O)NCCOC(=O)c1cccnc1
Product: CN1C=CC=[CH2+]C1C(=O)OCCNC(=O)N(CCF)N=O
Product: [I-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of the product of Example 125 (1.56 g, 5.4 mmol) in 40 mL of tetrahydrofuran was treated with excess methyl iodide. The mixture was stirred at 50° C. for 4 hours. The finely crystalline, yellow solid thus obtained (2.20 g, 94.1%) melted at 123°-125° C. and had the structural formula ##STR153##
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[N:3]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:12])=[CH:9][CH:8]=2)[N:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccn(-c2ccc(C(=O)Cl)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 4-(3-methylpyrazol-1-yl)benzoyl chloride was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.55 g) and diisopropylethylamine (0.44 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and a saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.90 g) was obtained as an amorphous solid, MS, m/z: 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:13]=1[C:14]([OH:16])=[O:15].CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:24][C:17]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([Cl:1])[CH:3]=2)[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1Cl
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1Cl

Procedure:
A mixture of 30 g of 3-chloro-4-methoxyaniline, 18.9 g of 2,6-dichloro-3-nitrobenzoic acid, and 150 ml N,N-dimethylaniline was heated at 100° under nitrogen for 24 hours. The reaction mixture was dissolved in chloroform and washed with dilute ammonium hydroxide. After the aqueous layer was washed with chloroform, it was acidified and the resulting orange solid was collected to provide 6-chloro-2[(3-chloro-4-methoxyphenyl)amino]-3-nitrobenzoic acid, mp 222°-228° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([O:11][C:12](=[O:35])[CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:15][CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:35]
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCC=Cc1ccccn1
Yield: 40 %

Procedure:
2-Pyridinecarbaldehyde (3.0 g, 28.0 mmol) and (4-ethoxy-4-oxobutyl)triphenylphosphonium (16.7 g, 36.5 mmol) were dissolved in 1,4-dioxane (60 ml), and a solution of potassium carbonate (5.8 g, 42.0 mmol) in water (6 ml) was added thereto. The reaction mixture was refluxed for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give Z-form of the titled compound (2.3 g, 40%). And the fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give E-form of the titled compound (1.2 g, 21%).
Reaction SMILES: [CH2:1](S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S[CH2:17][CH:18]([CH2:22][C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:19]([OH:21])=[O:20])C1C=CC=CC=1.O[O:30][S:31]([O-:33])=O.[K+]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH:26]([NH:25][C:23](=[O:24])[CH2:22][CH:18]([CH2:17][S:31]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])=[O:30])[C:19]([OH:21])=[O:20])([CH3:28])[CH3:27]
Reactant: O=S([O-])OO
Reactant: CC(C)NC(=O)CC(CSCc1ccccc1)C(=O)O
Reactant: SCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)CC(CS(=O)(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of itacconic anhydride (1.1209 g, 10 mmol) in 10 ml of methylene chloride at 0° C. was added drop wise isopropyl amine (0.85 ml, 10 mmol). The reaction was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure to give 2-(isopropylcarbamoyl-methyl)-acrylic acid. The residue was dissolved in 10 ml of DMF, then benzyl mercaptan (1.17 g, 10.0 mmol) and DMAP (122 mg, 1 mmol) were added and the reaction was stirred at room temperature for overnight. The mixture containing 2-benzylsulfanylmethyl-N-isopropyl-succinamic acid was cooled to 0° C. and oxone® (4.9182 g, 8 mmol) in 20 ml of water was added and stirred for 2 hours at room temperature. More oxone® was added and the reaction was stirred at room temperature for 18 hours. The reaction was filtered and the white solid was washed with water, ether and dried under high vacuum to give 1.0 grams of N-isopropyl-2-benzylsulfonylmethyl-succinamic acid, which was used without further purification; LCMS retention time 2:32 minutes: MS+1 (328.1).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([O:14][CH3:15])[CH:8]=2)[CH2:3][CH2:2]1.[H][H].C[CH2:19][OH:20]>[Pd]>[CH3:15][O:14][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:13]=[CH:12][C:10]=1[NH:11][CH:19]=[O:20]
Reactant: CCO
Reactant: [H][H]
Reactant: COc1cc(C2=CCOCC2)ccc1N
Agent: [Pd]
Product: COc1cc(C2CCOCC2)ccc1NC=O
Yield: 70 %

Procedure:
A solution of 4-(3,6-dihydro-2H-pyran-4-yl)-2-methoxyaniline (Preparation 156, 206 mg, 1.004 mmol) in EtOH (10 mL) was treated with Pd/C (10% w/w, 50 mg, 0.047 mmol) and stirred in an atmosphere of hydrogen for 36 hours. The suspension was filtered over celite and concentrated in vacuo. The residue was dissolved in formic acid (6 mL) and heated to reflux for 2 hours. The solution was concentrated in vacuo and azeotroped with toluene twice. The residue was purified by silica gel column chromatography eluting with 0 to 30% EtOAc in cyclohexanes to give the title compound (165 mg, 70%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:29]=O>C1(C)C=CC=CC=1.C(OCC)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:21]=[C:20]1[O:22][CH2:29][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[C@H:19]1[CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: O=C(N[C@@H](Cc1cscn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: C=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1OCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]1Cc1cscn1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(thiazol-4-yl)propanoic acid (Fmoc-Ala(4-Thz)-OH, Compound SP818) (50 g, 127 mmol), camphorsulfonic acid (2.10 g, 9.04 mmol) and paraformaldehyde (110 g, 3.66 mol) were dissolved in toluene (2 l) under a nitrogen atmosphere, and the mixture was stirred at 80° C. for two days. The reaction solution was diluted with diethyl ether and sequentially washed with an aqueous sodium bicarbonate solution and brine. The resulting organic extract was dried over sodium sulfate and then concentrated under reduced pressure to afford (S)-(9H-fluoren-9-yl)methyl 5-oxo-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (Compound SP817) (40.0 g, 98%) as a crude product.