Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Br:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)Nc1cccc(Br)c1
Yield: 66.2 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 3-bromophenyl isocyanate (0.0095 mL, 0.076 mmol) were reacted to give the title compound as an off-white solid (22.4 mg, 66%). 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 8.85 (s, 1H), 8.72 (s, 1H), 7.97-7.99 (m, 1H), 7.85 (t, J=1.9 Hz, 1H), 7.42-7.45 (m, 3H), 7.29-7.31 (m, 1H), 7.21-7.27 (m, 3H), 7.13-7.15 (m, 1H), 7.05-7.08 (m, 1H), 7.01 (d, J=7.9 Hz, 1H), 4.20-4.24 (m, 1H), 3.70-3.75 (m, 1H), 3.52-3.59 (m, 2H), 2.94-3.00 (m, 1H).
Reaction SMILES: [C:1]([C:4]1O[C:6]([CH3:15])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)(=O)[CH3:2].[CH2:16]([NH2:19])[CH2:17][NH2:18].O.[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:2][C:1]1[C:4]2[N:18]([C:6]([CH3:15])=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:8]=2)[CH2:17][CH2:16][N:19]=1
Reactant: NCCN
Reactant: CC(=O)c1cc(-c2ccccc2)c(C)o1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CCO
Product: CC1=NCCn2c1cc(-c1ccccc1)c2C

Procedure:
2-Acetyl-5-methyl-4-phenylfuran (1.9 g) was heated to 150° C. for 1 hour under argon with 6.3 ml of 1,2-ethanediamine and 0.6 ml of water. After cooling the mixture was poured into 500 ml of water and the mixture was extracted three times with 80 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 1.9 g of brown oil, was chromatographed on 100 g of aluminium oxide (neutral, III) with methylene chloride as the eluent. 0.6 g of a total of 1.2 g (56%) of crude product were dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.4 g of 3,4-dihydro-1,6-dimethyl-7-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt: 180°-182° C. (dec.).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC)=O)[C@@H:6]([CH3:16])[CH2:5]1)[CH:2]=[CH2:3].[OH-].[K+].C(=O)=O.C1(C)C=CC=CC=1>C(O)C>[CH2:1]([N:4]1[CH2:5][C@@H:6]([CH3:16])[NH:7][CH2:8][C@@H:9]1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N(C(=O)OCC)C[C@H]1C
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=CCN1C[C@@H](C)NC[C@@H]1C
Temperature: 100 °C
Yield: 69 %

Procedure:
Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 mol) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 mol) in 4300 mL of 95% ethanol and heated at reflux for 1.5 hours. Carbon dioxide evolution was observed for the first 0.5-1 hour of heating. The reaction was cooled below reflux temperature and 2000 mL of toluene was carefully added. Ethanol was removed by azeotropic distillation at 105° C., while adding an additional 4000 mL of toluene to the reaction flask during the course of the distillation. After collection of 9000 mL of distillate, the reaction was cooled to 100° C. and 1000 mL of toluene was carefully added. The solution was slowly cooled to 5° C. and maintained at 5° C. for 30 minutes. The solution was filtered, washing the filter cake with an additional 1500 mL of toluene. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate, and the solvent was removed to give 296 g (69%) of trans-1-allyl-2,5-dimethylpiperazine as a dark liquid.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].Cl[CH:8]([Cl:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>O1CCCC1>[Cl:16][C:8]1([O:5][C:4]1([CH:1]([CH3:3])[CH3:2])[CH3:6])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Reactant: CC(=O)C(C)C
Solvent: C1CCOC1
Product: CC(C)C1(C)OC1(Cl)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of 122 g of potassium tert.-butylate in 720 ml of tetrahydrofuran was added at -20°C with stirring under an inert atmosphere to a mixture of 95 g of methyl isopropyl ketone and 185 g of tert.butyl dichloroacetate and after returning the temperature to room temperature, the mixture was stirred for 2 hours. The mixture was poured into ice water and the mixture was stirred and the organic phase was separated. The organic phase was washed with aqueous sodium chloride solution, dried over magnesium sulfate, passed through vegetable charcoal and concentrated to dryness to obtain 230.4 g of tert.butyl 2-chloro-2,3-epoxy-3-isopropyl-butanoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:18])([F:17])[CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])[NH2:5].[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCCl.ClC(Cl)C>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([NH:5][C:27]([NH:26][C:24](=[O:25])[C:23]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=2[F:21])=[O:28])[CH:6]=[C:7]([Cl:19])[C:8]=1[O:9][C:10]([F:17])([F:18])[CH:11]([F:16])[C:12]([F:14])([F:15])[F:13]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1F
Temperature: 40 °C
Yield: 83.4 %

Procedure:
To a solution of 1.31 g 3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy) aniline in 5 mL 1,2-dichloroethane under an atmosphere of nitrogen at room temperature was added 0.87 g 2,6-difluorobenzoyl isocyanate dissolved in 10 mL dichloroethane dropwise over a 10 minute period. The mixture was stirred, warmed to 40° C. for a one hour period, then concentrated under vacuum to a brown solid 2.0 g. The mixture was chromatographed using a Michel-Miller low pressure silica gel column eluted with 4:1 dichloromethane/heptane. Like fractions were pooled and concentrated under vacuum to give 1.67 g of a light tan solid, mp 156°-7° C. Proton and 19F nmr spectra were consistent with the proposed structure. Anal. calcd C17H7Cl2F9N2O3 : C, 38.58; H, 1.33; N, 5.29. Found: C, 38.64; H, 1.40; N, 5.44.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22].Cl.O1CCOCC1>CO.O1CCOCC1>[CH3:11][O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)Cc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1C
Temperature: 100 °C
Reaction time: 54 h

Procedure:
A mixture of 2-chloro-3-nitro-pyridine (1.5 g, 9.46 mmol), (4-amino-2-methyl-phenyl)-acetic acid methyl ester (3.39 g 18.9 mmol, 2 equiv), and a 4 N solution of HCl in dioxane (6.9 mL, 28.0 mmol, 2.9 equiv) in MeOH/dioxane (30 mL; 1:1, v/v) is stirred for 54 h at 100° C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in EtOAc, washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (CH2Cl2/MeOH, 1:0→98:2) provides the title compound: ES-MS: 302.1 [M+H]+; tR=4.79 min (System 1); Rf=0.43 (CH2Cl2).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]=[CH:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[C:24]1([C:30]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:34][C:33]3[CH:35]=[CH:36][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:38][C:32]=3[O:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([S:39]([C:37]3[CH:36]=[CH:35][C:33]4[O:34][C:30]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[O:31][C:32]=4[CH:38]=3)(=[O:40])=[O:41])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(C2C=CNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
4-(4-Chlorophenyl)-1,2,3,4-tetrahydropyridine hydrochloride (19.37 mg, 0.10 mmol) was suspended in methylene chloride (2 ml). Ethyldiisopropylamine (0.035 ml, 0.20 mmol) was added and the solution was shaken for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (37.28 mg, 0.10 mmol) was added and the reaction was shaken at room temperature for 12 hours. Aqueous HCl (0.1 N, 1.0 ml) was added and the mixture shaken for 30 minutes, the aqueous layer removed and the organic phase concentrated and purified by preparative reverse phase HPLC (YMC, ODS-AQ packing; 20%→95% CH3CN/H2O) to yield the sulfonamide (2.6 mg, 5%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[NH:20][C:19]=2[CH3:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].F[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>CN(C=O)C>[C:38]([N:20]1[C:21]2[C:26](=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:18]([CH2:17][CH2:16][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[CH2:9][CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:19]1[CH3:29])(=[O:39])[C:37]1[CH:41]=[CH:42][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CCCC3CCCCC3)c2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CCCC1CCCCC1)c(C)n2C(=O)c1ccccc1

Procedure:
Reaction of 3-{2-[2-(3-cyclohexylpropyl)piperidino]ethyl}-5-methoxy-2-methylindole with a mineral oil dispersion of sodium hydride in DMF and reaction of the resulting sodium salt with 4-fluorobenzoyl chloride affords 1-benzoyl-3-{2-[2-(3-cyclohexylpropyl)piperidino]ethyl}-5-methoxy-2-methylindole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Yield: 94.6 %

Procedure:
0.2 g (0.00105 mol) of 1-benzyl-4-hydroxypiperidine and 0.26 ml (0.00184 mol) of triethylamine were dissolved in 10 ml of toluene and treated with 0.11 ml (0.00084 mol) of 2-chloro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.262 g (95%) of 1-benzyl-piperidin-4-yl 2-chloro-benzoate was obtained as white crystals; m.p. 143°-144°.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:4]1[C:5]2[C:10](=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c([N+](=O)[O-])cccc2c[n+]1[O-]
Product: Cc1cc2c([N+](=O)[O-])cccc2c(Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3-methyl-5-nitro-isoquinoline-2-oxide (12 g) was added to phosphorus oxychloride (60 ml) and the mixture was refluxed with stirring for 1 hour, and then allowed to cool to room temperature (20°C). The reaction mixture was then poured onto ice, and the crude product, weighing 6.2 g, was isolated by filtration. This product was then recrystallized twice from acetone to yield 1-chloro-3-methyl-5-nitro-isoquinoline melting at 112°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3cc(C(=O)O)nc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A 100 mL round bottom flask was charged with ethyl 8-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,2-a]pyrazine-2-carboxylate (prepared as described in Example 61 steps 1-5, 0.80 g, 1.75 mmol), LiOH (0.22 g, 5.25 mmol), water (2 mL) and THF (30 mL). The mixture was stirred at 25° C. for 16 h. Reaction progress was monitored by LC-MS. Work-up: the solvent was evaporated. The residue was acidified with 2 N HCl. The precipitate was collected by filtration and dried, to afford 0.57 g (76%) of the product. MS m/z: 428 (M−H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:13])[CH:11]=[CH2:12])=[CH:5][CH:4]=1.[OH:14][C:15]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:16]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][CH3:26])[CH2:21][CH2:20]1)=[O:17]>O1CCCC1>[OH:14][C:15]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)[C:16]([O:18][C@H:19]1[CH2:20][CH2:21][C@H:22]([N:25]([CH2:12][CH2:11][C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=2)=[O:13])[CH3:26])[CH2:23][CH2:24]1)=[O:17]
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Reactant: C=CC(=O)Nc1ccc(CO)cc1
Solvent: C1CCOC1
Product: CN(CCC(=O)Nc1ccc(CO)cc1)[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Temperature: 75 °C
Reaction time: 96 h

Procedure:
To a solution of N-[4-(hydroxymethyl)phenyl]acrylamide (intermediate 79; 0.3 g, 1.7 mmol) in tetrahydrofuran (6 mL) was added trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 0.5 g, 1.42 mmol). The mixture was placed in a sealed vessel and stirred for 4 days at 75° C. The solvent was removed under reduced pressure and the crude obtained was purified by preparative reversed-phase HPLC (System 2) to give the title compound (34%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].N1C=CC=CC=1.[Cl:39][CH2:40][C:41]1[S:42][CH:43]=[C:44]([C:46](Cl)=[O:47])[N:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:39][CH2:40][C:41]1[S:42][CH:43]=[C:44]([C:46]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[O:47])[N:45]=1
Reactant: O=C(Cl)c1csc(CCl)n1
Reactant: COc1ncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
N-[5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (700 mg, 1.478 mmol) was dissolved in DCM (30 ml) and cooled to 0° C. before pyridine (0.179 ml, 2.217 mmol) was added. To this mixture was added 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (290 mg, 1.478 mmol) as a solution in DCM (10 ml) dropwise over 15 mins. The mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium bicarbonate solution (20 ml) was added to the mixture and it was stirred vigorously for 10 mins. The organic layer was separated using a hydrophobic frit, washed with water (20 ml) and concentrated in vacuo to give the title compound as an orange solid (697 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12]/[N:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[N+]([C:23]([CH2:50][CH2:51][CH2:52][CH3:53])=[CH:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][C:26]=1[C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41]1)=[O:39])([O-])=O>>[C:32]([O:31][C:29]([C:28]1[CH:36]=[CH:37][C:25]([C:24]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)[C:23]=2[CH2:50][CH2:51][CH2:52][CH3:53])=[C:26]([C:38]([N:40]2[CH2:49][CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41]2)=[O:39])[CH:27]=1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCCOc1ccc(N/N=C/C(=O)OCC)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCOc1ccc(-n2nc(C(=O)OCC)c(-c3ccc(C(=O)OC(C)(C)C)cc3C(=O)N3CCc4ccccc4C3)c2CCCC)cc1
Yield: 69.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-butoxyphenyl)hydrazono)acetate (51 mg, 0.19 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (90 mg, 0.19 mmol) were converted to the title compound (90 mg, 68%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.11 (dd, J=8, 2 Hz, 1H), 8.07-8.05 (m, 1H), 7.46-6.88 (m, 9H), 5.02-4.98 (m, 1H), 4.48-4.38 (m, 1H), 4.33-4.28 (m, 2H), 4.18-3.98 (m, 3H), 3.58-3.32 (m, 1H), 2.85-2.50 (m, 4H), 1.85-1.79 (m, 2H), 1.61 (s, 9H), 1.59-1.51 (m, 2H), 1.31 (t, J=8 Hz, 1.5H), 1.23 (t, J=8 Hz, 1.5H), 1.13-0.95 (m, 7H), 0.65-0.60 (m, 3H); MS(ESI+) m/z 680.3 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCC1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC1CCNC1

Procedure:
3.1 g (0.0t mol) (3RS)-1-benzyl-3-(N-tert-butyloxycarbonylaminoethyl) pyrrolidine was hydrogenated at 0.28 MPa over 0.6 g of Pearlman's catalyst (Pd(OH)2) in 40 ml ethanol (95%) over night. After filtration of the catalyst through cellite and evaporation of the solvent 1H-NMR showed that the reaction was not completed. Therefore 0.6 g of Pearlman's catalyst was added in 40 ml ethanol (95%) once more and the mixture was treated under H2 -atmosphere at 0.28 MPa over night. Filtration through cellite and evaporation of the solvent gave the product in a quantitative yield (2.18 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25](O)=[O:26])([O-:3])=[O:2].C(Cl)Cl.ClC(OC)=O.[NH3:36]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25]([NH2:36])=[O:26])([O-:3])=[O:2]
Reactant: O=C(O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: N
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
88 g of N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-3-aminopropionic acid (compound 3) are added to 500 ml of methylene chloride with 34.3 ml of triethylamine at -25° C. With stirring, 22.8 ml of methyl chloroformate are run in over 30 minutes and stirring is continued at -10° to -20° C. After 2 hours, 40 ml of ammonia solution are added and the reaction mixture is warmed to room temperature. The mixture is then washed with water and the organic phase is concentrated. The residue is recrystallised from ethyl acetate/hexane. The product has a melting point of 137°-138° C.
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>>[Br:22][CH2:23][CH2:24][C:25]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:26]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reactant: O=C(Cl)CCBr
Product: O=C(CCBr)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Yield: 65 %

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (5 g, 0.018 mol) was reacted according to the procedure of Example 9 with 3-bromopropionyl chloride (6.8 g, 0.04 mol, 4 mL) using a bath temperature of 100° C. A white crystalline product was obtained in 65% yield (4.9 g), m.p. 133°-134° C. Anal. calc. for C19H17N2O4Br: C, 54.69; H, 4.11; N, 6.72; Br, 19.15. Found: C, 54.79; H, 4.12; N, 6.69; Br, 19.25. The product had the formula: ##STR74##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[NH2:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[OH:40][C:36]1[CH:35]=[C:34]([NH:33][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[O:31])[CH:39]=[CH:38][CH:37]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)Nc5cccc(O)c5)c34)n(-c3ccccc3)c(=O)c12
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (25 mg, 0.06 mmol), 3-aminophenol (7 mg, 0.07 mmol) and diisopropylethylamine (41 μl, 0.23 mmol) were dissolved in DMF (1.5 ml) and stirred for 30 min. The reaction flask was then sealed and T3P® (50% in DMF, 140 μl, 0.24 mmol) was added dropwise and the reaction mixture stirred overnight at room temperature. The mixture was poured into ice and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 5% DCM/MeOH) to give 2 mg (6% yield) of the title compound as a white solid.