Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].[CH2:11](OCl)[CH2:12][CH2:13]C.CC[C:19](=[S:21])C.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([CH3:10])=[C:5]2[C:3]=1[NH:4][C:12]([CH3:13])=[C:11]2[S:21][CH3:19]
Reactant: CCC(C)=S
Reactant: CCCCOCl
Reactant: Cc1cc(N)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1c(C)[nH]c2c(Cl)cc(F)c(C)c12
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
A stirred solution of 2-chloro-4-fluoro-5-methylaniline (1.655 g) in methylene chloride (100 ml) under nitrogen was treated at −65° C. with a solution of butylhypochlorite (1.126 g) in methylene chloride (5 ml), stirred at −65° C. for 10 min, treated at −65° C. with a solution of methylthioacetone (1.080 g) in methylene chloride (5 ml) stirred at −65° C. for 1 hour, treated at −65° C. with triethylamine (1.05 g) and allowed to reach ambient temperature. The solution was washed, dried (MgSO4) and evaporated. The residue was purified by silica chromatography using 25% acetone in isohexane as eluent to give the sub-title compound (1.704 g).
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.Cl[CH2:11][CH2:12][OH:13].[Cl:14][C:15]1[CH:40]=[CH:39][C:18]2[N:19]3[C:23]([CH2:24][NH:25][CH2:26][C:17]=2[CH:16]=1)=[N:22][N:21]=[C:20]3[CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1>CN(C)C=O>[NH3:4].[Cl:14][C:15]1[CH:40]=[CH:39][C:18]2[N:19]3[C:23]([CH2:24][N:25]([CH2:11][CH2:12][OH:13])[CH2:26][C:17]=2[CH:16]=1)=[N:22][N:21]=[C:20]3[CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:34]=[CH:35][CH:36]=[CH:37][N:38]=2)[CH2:29][CH2:28]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Reactant: CCN(C(C)C)C(C)C
Reactant: OCCCl
Solvent: CN(C)C=O
Product: N
Product: OCCN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
N,N-Diisopropylethylamine (80 μl, 0.62 mmol), followed by 2-Chloroethanol (52 μl, 0.78 mmol) were added to a solution of the amine from example 12 (200 mg, 0.52 mmol) in N,N-dimethylformamide (6 ml), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate:methanol:0.88 ammonia (90:10:1) as eluant, to give the title compound as an off-white solid (120 mg).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(F)(F)F)c2)C(N)C1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Product: NC(=O)c1ccnc2c(NC3CNCCC3c3cccc(C(F)(F)F)c3)ncnc12

Procedure:
Compound 24 was prepared following general synthesis scheme 9 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.78 (d, 1H), 9.06 (d, 1H), 9.03-8.95 (m, 1H), 8.90 (d, 1H), 8.88-8.73 (m, 1H), 8.50 (s, 1H), 8.32 (d, 1H), 8.16 (d, 1H), 7.62 (s, 1H), 7.56 (q, 1H), 7.43 (d, 2H), 5.22-5.02 (m, 1H), 3.60-3.38 (m, 3H), 3.14 (q, 1H), 2.99 (q, 1H), 2.54 (d, 1H), 2.08 (dt, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.N/[C:10](=[CH:15]\[CH3:16])/[C:11](OC)=[O:12]>>[OH:8][C:7]1[C:2]2=[N:1][C:15]([CH3:16])=[CH:10][C:11](=[O:12])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: C/C=C(\N)C(=O)OC
Product: Cc1cc(=O)n2cccc(O)c2n1
Yield: 79.6 %

Procedure:
A mixture of 110.0 g of 2-amino-3-pyridinol and 130.0 g of methyl 2-aminocrotonate are heated at an internal temperature of 110°-115° for approximately 4 hours. The solid product is sublimed in vacuo to give about 140.0 g of product, m.p. 144°-145°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])[C:5]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[N:19][C:4]=3[CH:3]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(COCC[Si](C)(C)C)c12)[C@H]1CNC(=O)C1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc3ncn(COCC[Si](C)(C)C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 25 °C

Procedure:
Into the solution of (R)-4-((R)-1-(6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.12 (267 mg, 0.65 mmol) and 3,4-dimethoxyphenylboronic acid (142 mg, 0.78 mmol) in 2:1 DME:water (10 ml) was added cesium carbonate (3 equiv), and PEPPSI-IPr catalyst (0.1 equiv). Mixture was refluxed for 3 h, cooled to room temperature, poured into water and extracted with ethyl acetate (100 mL). Separated organic layer was washed with Brine (2×50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to yield residues which were purified by silica gel column chromatography to isolate (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.08.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:28]=[C:29]([N:33]2[C:38](=[O:39])[C:37]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[N:36][C:35]3[CH:47]=[CH:48][CH:49]=[N:50][C:34]2=3)[CH:30]=[CH:31][CH:32]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O1CCOCC1.C(OCC)(=O)C>[CH2:40]([C:37]1[C:38](=[O:39])[N:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([NH:26][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:13])[CH:28]=2)[C:34]2[N:50]=[CH:49][CH:48]=[CH:47][C:35]=2[N:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
A mixture of 2-quinolinecarboxylic acid (520 mg) and 1,1′-carbonyldiimidazole (243 mg) in tetrahydrofuran (5 ml) was stirred at room temperature for 1.5 hours. A solution of 4-(3-aminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido[2,3-b]pyrazine (493 mg) in 1,4-dioxane (5 ml) was added to the mixture and stirring was continued for 5 days. The reaction mixture was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate, concentrated, and subjected to silica gel column chromatography (hexane-ethyl acetate, 1:1) to afford 2-benzyl-3-oxo-4-[3-(quinolin-2-yl) carbonylaminophenyl]-3,4-dihydropyrido[2,3-b]pyrazine (87 mg) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>>[CH:8]1([NH:7][C:5](=[O:6])[C:4]2[CH:14]=[CH:15][CH:16]=[C:2](/[CH:19]=[CH:18]/[CH2:17][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: O=C(NC1CCCCC1)c1cccc(Br)c1
Product: O=C(NC1CCCCC1)c1cccc(/C=C/CNC(=O)C(F)(F)F)c1

Procedure:
Heck coupling of 3-bromo-N-cyclohexylbenzamide and N-allyl-2,2,2-trifluoroacetamide following the method described in Example 118 gave (E)-N-cyclohexyl-3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)benzamide as a light yellow solid. Yield (0.50 g, 71%): 1H NMR (400 MHz, CD3OD) δ 8.18-8.26 (m, 1H), 7.83 (t, J=1.6 Hz, 1H), 7.65-7.68 (m, 1H), 7.54-7.56 (m, 1H), 7.39 (t, J=7.6 Hz, 1H), 6.62 (d, J=16.0 Hz, 1H), 6.32 (dt, J=16.0, 6.4 Hz, 1H), 4.06 (d, J=5.6 Hz, 2H), 3.80-3.90 (m, 1H), 1.93-1.95 (m, 2H), 1.79-1.82 (m, 2H), 1.66-1.70 (m, 1H), 1.18-1.48 (m, 5H).
Reaction SMILES: [OH-].[NH4+:2].[Cl-].[NH4+:4].[C-:5]#N.[Na+].[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1>>[NH2:2][C:11]1([C:5]#[N:4])[CH2:12][CH2:13][O:8][CH2:9][CH2:10]1
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: N#CC1(N)CCOCC1
Temperature: -7 °C
Reaction time: 18 h

Procedure:
8 ml of ammonium hydroxide, 1.58 g of ammonium chloride and 1.23 g of sodium cyanide were successively introduced and the solution obtained was cooled in an ice/methanol bath at about -7° C. 2 ml of tetrahydro-4H-pyran-4-one were added at a temperature of ≤0° C., and the reaction medium was allowed to rise to ambient temperature with vigorous stirring for 18 hours. After extracting 3 times with methylene chloride, washing with salt water and drying, 2.49 g of the expected product (translucent crystals) melting at approximately 46-47° C. were obtained.
Reaction SMILES: C([C:5]([O:7][CH2:8]CC(O)C)=[O:6])(C)(C)C.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15]C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:8][O:7][CH2:5][O:6][C@@H:16]1[CH2:15][C@@H:13]([OH:19])[CH:18]=[CH:17]1
Reactant: CC(O)CCOC(=O)C(C)(C)C
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCO[C@H]1C=C[C@H](O)C1
Reaction time: 0.33 h
Yield: 151.6 %

Procedure:
To a solution of 3.47 g (19.9 mmol) of alcohol 25 (prepared in 30-(1)), 2.81 g (29.9 mmol) of phenol, and 7.88 g (29.9 mmol) of triphenylphosphine in 100 ml of dry THF is added a solution of 4.65 ml of diethyl azodicarboxylate in 40 ml of dry THF dropwise under ice cooling. After additional stirring at the same temperature for 20 minutes, the mixture is stirred for further 2 and half hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (200 g of silica gel, ethyl acetate:n-hexane=1:49 to 1:19) to give 4.35 g of the desired phenyl ether 3 as an oil in 87.4% yield.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:20]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH2:17][C:11]=2[CH:10]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.[CH2:36](O)[CH2:37][OH:38]>CCOC(C)=O>[CH3:8][C:9]1[C:20]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][C:16]3([CH2:17][C:11]=2[CH:10]=1)[O:38][CH2:37][CH2:36][O:18]3
Reactant: OCCO
Reactant: CC(=O)Nc1cc2c(cc1C)CC(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc2c(cc1C)CC1(CCC2)OCCO1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
In a 50 L mechanically stirred vessel with Dean-Stark trap, toluene (22 L) was added to N-(3-methyl-6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetamide (77) (1.04 kg, 4.50 mol). TosOH (84.0 g, 442 mmol) and ethylene glycol (750 mL, 13.4 mol) were added. The resulting mixture was heated to reflux overnight, cooled to rt, diluted with EtOAc (12 L) and washed with sat. aq. NaHCO3 (12 L) and sat. aq.s NaCl (12 L). The combined aq. washes were extracted with DCM (2×8 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel. The product containing fractions were combined and concentrated under reduced pressure to afford N-(3-methyl-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-[1,3]dioxolan]-2-yl)acetamide (78) (900 g, 73% yield). 1H NMR (300 MHz, CDCl3): δ 7.45 (s, 1H), 7.03 (s, 1H), 6.92 (s, 1H), 3.96 (m, 4H), 3.02 (s, 2H), 2.76 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 1.98 (m, 2H), 1.74 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.[CH3:8][C@@H:9]([NH2:14])[CH2:10][CH2:11][CH2:12][CH3:13]>CO.[Pd]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:14][C@@H:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH3:8]
Reactant: COC(C=O)OC
Reactant: CCCC[C@@H](C)N
Agent: [Pd]
Solvent: CO
Product: CCCC[C@@H](C)NCC(OC)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2,2-Dimethoxyacetaldehyde (7.54 mL) was added to a solution of (R)-hexan-2-amine (5.06 g) in methanol (20 mL) and the mixture stirred at ambient temperature for 5 h. A slurry of 10% palladium on carbon (200 mg) in methanol (5 mL) was added and the mixture hydrogenated at 5 bar for 16 h, then filtered and concentrated in vacuo to afford the sub-titled compound as a colourless liquid (9.22 g). 1H NMR (400 MHz, CDCl3) δ 4.46 (t, J=5.5 Hz, 1H), 3.39 (s, 6H), 2.72 (ddd, J=31.1, 11.9, 5.6 Hz, 2H), 2.60 (sextet, J=6.0 Hz, 1H), 1.36-1.24 (m, 6H), 1.04 (d, J=6.2 Hz, 3H), 0.90 (t, J=6.9 Hz, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:13][N:14]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][C:18]=2[S:17](=[O:32])(=[O:31])[C:16]([C:33](OC)=[O:34])=[N:15]1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:33]([C:16]2[S:17](=[O:31])(=[O:32])[C:18]3[CH:23]=[C:22]([CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:21]=[CH:20][C:19]=3[N:14]([CH3:13])[N:15]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: COC(=O)C1=NN(C)c2ccc(CN3CCOCC3)cc2S1(=O)=O
Reactant: NCc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 70 °C
Yield: 83 %

Procedure:
4-Chlorobenzylamine (0.66 mL) and a 0.5 M solution of NaOMe in CH3OH (0.060 mL) is added to a solution of methyl 1-methyl-6-(4-morpholinylmethyl)-1H-4,1,2-benzothiadiazine-3-carboxylate 4,4-dioxide (Preparation 41, 0.16 g) in CH3OH (15 mL) at room temperature. The mixture is heated for 12 hours at 70° C. and then the solvent is evaporated. The crude material is triturated with CH3CN and the organic layer is decanted. The remaining solid is chromatographed with MeOH/CH2Cl2 (1-5%) to obtain 0.174 g (83%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 463 (M+H).
Reaction SMILES: C(O)C.[O:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]2[CH:16]=[N:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:8]2[C@@H:7]2[CH2:24][CH2:25][CH2:26][N:6]12.[OH-].[Na+].[C:29](=[N:32]O)([NH2:31])[CH3:30]>O.Cl.CN(C)C=O>[CH3:30][C:29]1[N:32]=[C:19]([C:18]2[N:17]=[CH:16][N:9]3[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5](=[O:4])[N:6]4[CH2:26][CH2:25][CH2:24][C@H:7]4[C:8]=23)[O:21][N:31]=1.[C:19]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:18]
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: CC(N)=NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(C)=O
Product: Cc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2ccccc2-3)n1

Procedure:
40 ml of ethanol and 14.0 g (44.9 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are added to a solution of 2.21 g (55.2 mmol) of sodium hydroxide in 10 ml of water and the mixture is stirred at boiling temperature for 30 minutes. The mixture is diluted with 40 ml of water and neutralized with 13.8 ml of 4N hydrochloric acid. After evaporation of the ethanol in a water-jet vacuum the suspension is filtered; the filter residue is rinsed with water and dried at 90° in a high vacuum. The product obtained is suspended in 60 ml of N,N-dimethylformamide, 9.40 g (56 mmol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred at 60° overnight. The reaction mixture is treated with 3.65 g (49.3 mmol) of acetamidoxime and stirred at 60° for a further 2 hours. The mixture is evaporated to dryness, the residue is dissolved in 50 ml of glacial acetic acid and the solution is heated to 120° for 2.5 hours. The yellow solution is concentrated; the residue is taken up in methylene chloride and washed with a saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate, evaporated and there is obtained by recrystallization of the residue from methylene chloride and ethyl acetate (S)-11,12,13,13a-tetrahydro-1-(3-methyl-1,2,4-oxadiazol-5-yl)-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 180°-182°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]2S[CH:21]=[CH:22][N:23]=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl:34][C:35]1N=CC=C[N:36]=1>>[ClH:34].[CH3:2][O:3][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:36]=[CH:35][CH:21]=[CH:22][N:23]=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1ncccn1
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCCNc2nccs2)[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccccc1CN[C@H]1CCCN(CCCCNc2ncccn2)[C@H]1c1ccccc1

Procedure:
The title compound was prepared in a similar manner to the compound of Example 1 by replacing 2-bromothiazole with 2-chloropyrimidine; mp 123°-127° C. (dec.) 1H NMR (CDCl3) 67 1.46 (m, 5H), 1.94 (m, 6H), 2.54 (m, 2H), 3.24 (m, 4H), 3.35 (d, 1H, J=15), 3.48 (s, 3H), 3.64 (d, 1H, J=15), 6.42 (t, 1H, J=5), 6.59 (d, 1H, J=9), 6.68 (t, 1H, J=6), 6.80 (d, 1H, J=6), 7.05 (t, 1H, J=9), 7.22 (m, 5H), 8.18 (d, 2H, J=5). HRMS calc'd for C27H35N5O: 445.2836. Found: 445.2813.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([NH:10][CH3:11])=[N:8][CH:9]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([N:10]([CH3:11])[S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[N:8][CH:9]=1
Reactant: CNc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ncc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in 2.0 ml of DMF, 5-chloro-2-methylamino-3-nitropyridine (0.20 g (1.07 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, p-toluenesulfonyl chloride (0.23 g (1.21 mmol)) was added. The reaction mixture was stirred under cooling with ice for 30 minutes and then at room temperature for 30 minutes, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.16 g (44%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl/[C:2](=[N:8]\[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].CS[C:20]1[NH:24][N:23]=[CH:22][N:21]=1.C(N(CC)CC)C>O1CCOCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:22]2=[N:23][N:24]=[CH:20][N:21]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]1
Reactant: CCOC(=O)/C(Cl)=N/NCc1ccccc1F
Reactant: CSc1ncn[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2nncn12

Procedure:
Ethyl(2Z)-chloro[(2-fluorobenzyl)hydrazono]acetate (807 mg, 3.12 mmol) from example 2A, 5-(methylthio)-1H-1,2,4-triazole (359 mg, 3.12 mmol) and triethylamine (316 mg, 3.12 mmol) are dissolved in dioxane (5 ml) and heated under reflux for 6 h. This is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the crude product is purified by chromatography on silica gel (eluent: dichloromethane/methanol 50:1). 124 mg (9.5% of theory) of the desired product are obtained with 69% purity.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH2:16])=[S:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][I:18]>CO>[IH:18].[CH3:17][S:15][C:14](=[NH:16])[NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: NC(=S)Nc1ccccc1N1CCCCC1
Solvent: CO
Product: CSC(=N)Nc1ccccc1N1CCCCC1
Product: I

Procedure:
A mixture of 1-(2-piperidinophenyl)thiourea (10.1 g), methyl iodide (5.35 g) and methanol (50 ml) was heated at 50°-55° C. for 2 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-piperidinophenyl)-2-thiopseudourea hydroiodide (m.p. 160°-162° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]

Procedure:
A stirred mixture of 5-fluoro-2-nitrophenol (100.0 gm, 0.64 mol), ethyl bromoacetate (77.6 mL, 116.9 gm, 0.78 mol) and K2CO3 (175.9 gm, 1.27 mol) in acetonitrile (800 mL), under N2, was heated to reflux for 1 hour. The reaction mixture was filtered and the filtrate was washed with brine (200 mL), dried (MgSO4) and evaporated to dryness to give the title compound of Step A, Example 3, as an orange solid (150.0 gm), 97%; m.p. 37°-39° C.; 1H NMR δ: 1.28-1.32 (t,3H), 4.23-4.29 (m,2H), 4.77 (s,2H), 6.64-6.68 (d,1H), 6.79-6.83 (t,1H), 7.96-8.01 (q,1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:15]C(=O)C)([O-:3])=[O:2].O.[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc(N2CCCC2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(N2CCCC2)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of N-(2-nitro-4-pyrrolidin-1-ylphenyl)acetamide obtained in step IV above (1.0 eq) in MeOH and water was added NaOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired 2-nitro-4-pyrrolidin-1-ylaniline. (Yield=85%)