Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].ClC(Cl)(Cl)[C:47]([N:49]=C=O)=[O:48].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:47]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:42])[CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:20][CH:21]=3)[C:12](=[O:43])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])(=[O:48])[NH2:49]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: O=C(Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
8 g of raw product of Step A were added with stirring at room temperature to a solution of 8 g of trichloroacetyl isocyanate in 160 ml of dry methylene chloride and after stirring for 15 minutes, 1.6 liters of a solution of aqueous 6% sodium bicarbonate were added thereto. The mixture was stirred at room temperature overnight and was then extracted with ethyl acetate. The organic phase was removed and the aqueous phase was acidified with 6 N hydrochloric acid to a pH of 2 in the presence of ethyl acetate. The organic phase was washed with water, dried and concentrated under reduced pressure to 30 ml. The product was precipitated by addition of isopropyl ether and the mixture was filtered and dried to obtain 2.7 g of 3-carbamoyloxymethyl-7β-[2-(2-tritylamino-4-thiazolyl)-acetamido]-ceph-3-eme-4-carboxylic acid melting at about 200° C. with decomposition.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[NH:26][C:25](=[O:27])[C:24]3[NH:28][CH:29]=[N:30][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[NH:26][C:25](=[O:27])[C:24]3[N:28]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:29]=[N:30][C:23]=3[CH:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3nc[nH]c3c(=O)[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c21
Reaction time: 8 h

Procedure:
ClCH2COOEt (1 equiv.) in dimethylforamide was added drop-wise to a solution of 4-(4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-6-yl)piperazine-1-carboxylic acid tert-butyl ester, 3 and potassium carbonate (0.8 equiv.) in dimethylforamide. The solution was stirred overnight. The mixture was then diluted with water and extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate, and the solvents were evaporated. The product was further purified over a silica column chromatography, eluting with ethyl acetate, to give 4 as a solid.
Reaction SMILES: Br.[OH:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Si:23]([O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cccc(-c2ncccc2O)c1
Agent: Br
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccnc1-c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a stirred suspension of 3-(3-hydroxypyridin-2-yl)nitrobenzene hydrobromide (0.3 g) and imidazole (165 mg) in N,N-dimethylformamide (3 ml) was added tert-butyldimethylsilyl chloride (183 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogencarbonate solution and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 3-(3-tert-butyldimethylsilyloxypyridin-2-yl)nitrobenzene (332 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1.[NH3:27].O1CCOCC1>>[NH2:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[N:5]=[C:4]([NH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Reactant: N
Solvent: C1COCCO1
Product: Cc1cc(C)c(Nc2nc(N)nc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 100 °C
Yield: 61.4 %

Procedure:
A mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]-amino]benzonitrile (*A9c) (0.00137 mol) and NH3 in 1,4-dioxane (0.5 M; 0.00548 mol) was heated in a pressure vessel at 100° C. for 6 days. The solvent was evaporated and the residue was dissolved in CH2Cl2, washed with a saturated aqueous NaHCO3 solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from toluene. The precipitate was filtered and dried, yielding 0.29 g (61.4%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile. b) As an alternative for the preparation of this compound, a mixture of 4-[[4-chloro-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile (0.0230 mol) in NH3 in 2-propanol (2.0 M; 60 ml) and NH3 in 1,4-dioxane (0.5 M; 20 ml) was heated at 95° C. for 21 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1 N NaOH, water and brine, dried, filtered and the filtrate was evaporated. The residue was recrystallized with acetonitrile, yielding 5.25 g (66.1%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C:14](O)=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC(C)(C)[CH2:26][C:27]([OH:29])=[O:28])=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13]/[CH:14]=[CH:26]/[C:27]([OH:29])=[O:28])[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CCC1
Product: CC(C)(C)OC(=O)NC1(C/C=C/C(=O)O)CCC1

Procedure:
(2E)-4-(1-(tert-Butoxycarbonylamino)cyclobutyl)but-2-enoic acid was synthesized starting with (1-(tert-butoxycarbonylamino)cyclobutyl)acetic acid analogously to the synthesis of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid starting with of 3-tert-butoxycarbonylamino-3-methylbutanoic acid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH2:24])=[NH:23])([O-:18])=[O:17]>>[OH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:24]=[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=2)[N:23]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)c1cnc(-c2cccc([N+](=O)[O-])c2)nc1O
Yield: 86 %

Procedure:
The title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (5 g, 24 mmol) with 3-nitrobenzamidine (5 g, 25 mmol) to afford 86% of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (6 g, 21 mmol) with (chloromethylene)dimethylammonium chloride (4 g, 31 mmol) concentration of reaction mixture, followed by hexane and ether wash afford 45% of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate, (c) reaction of ethyl 4-chloro-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.9 g, 6 mmol) with hydrazine (0.6 g, 18 mmol) to afford 33% of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3'-nitrophenyl)pyrimidine-5-carboxylate (1.8 g, 6 mmol) with citraconic anhydride in analogy to Example 21, to afford 80% (0.5 g) of the title compound; m.p. 118-120° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>C1C=CC=CC=1>[C:12]([NH:11][C:10]1[CH:9]=[C:8]([CH:20]=[CH:19][CH:18]=1)[NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(=O)Nc1cccc(N)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CCCCC(=O)Nc1cccc(NC(=O)CC(C)=O)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
42 g of diketene were added to a mixture of 96 g of m-aminovaleranilide in 400 ml of benzene and the mixture was stirred for 16 hours at 20° C. The benzene was decanted and the residue was added to refluxing benzene. The mixture was treated with activated carbon and filtered to obtain raw m-valeramido-acetylacetanilide melting at 90° C. Crystallization from ethyl acetate yielded 34 g of pure m-valeramido-acetylacetanilide melting at 116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH:22]=O.[OH-].[K+].[C:26]1([CH2:31][C:32]#[N:33])[CH2:30][CH2:29][CH2:28][CH:27]=1>CS(C)=O>[NH2:33][C:32]1[C:31]([C:26]2[CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:22][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([C:8]3[C:9]([CH3:21])=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:4]=2)[N:1]=1
Reactant: N#CCC1=CCCC1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc(N)c(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(C3=CCCC3)cc2c1

Procedure:
A solution of 4-amino-2′-methyl-6′-(pyrrolidine-1-carbonyl)biphenyl-3-carbaldehyde (0.040 g, 0.13 mmol, prepared as in Example 57, Steps 2-5), KOH (10.9 mg, 0.195 mmol) (11 M solution, 18 uL), 1-cyclopenteneacetonitrile (0.022 mL, 0.20 mmol) and DMSO (0.8 mL) was heated in a Biotage microwave at 140° C. for 5 min. LCMS indicated good conversion to desired product. The crude material was purified by prep HPLC (21-60% CH3CN/water modified with 0.1% TFA), and again by prep HPLC (10-90% CH3CN/water modified with 0.1% NH4OH) to give (2-(2-amino-3-cyclopentenylquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 398 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([C:33]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:36][C:34]=2[NH2:35])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:34]1[CH:36]=[C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:38]=[CH:39][C:33]=1[C:30]1[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[C:3]([CH3:24])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:23])(=[O:22])=[O:21])=[N:5]2
Reactant: COc1ccc(-c2ccc(N3CCOCC3)cc2N)cn1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccc3S(C)(=O)=O)nc3cc(F)cc(F)c23)cn1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (50.0 mg, 0.140 mmol) and 2-(6-methoxypyridin-3-yl)-5-morpholinoaniline in toluene to give 5,7-difluoro-N-(2-(6-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(2-(methylsulfonyl)-phenyl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.34 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=7.8 Hz), 7.73-7.83 (2H, m), 7.63-7.73 (1H, m), 7.40-7.47 (1H, m), 7.38 (1H, d, J=7.2 Hz), 7.14 (1H, d, J=8.4 Hz), 6.94 (1H, ddd, J=13.7, 8.6, 2.5 Hz), 6.86 (1H, d, J=13.7 Hz), 6.82 (1H, dd, J=8.5, 0.7 Hz), 6.55 (1H, d, J=7.4 Hz), 6.32 (1H, br. s.), 3.99 (3H, s), 3.78 (4H, t, J=4.2 Hz), 3.00-3.32 (7H, m), 1.96 (3H, s). Mass Spectrum (ESI) m/e=617.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: COc1ccccc1N
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccccc1Nc1cc(C)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and o-anisidine (27 μl, 0.243 mmol) similar to Example 13 and isolated as a pale white solid (40 mg, 56%). 1H NMR (CDCl3): 8.82–8.80 (m, 1H), 8.46 (d, J=8.1 Hz, 1H), 7.90 (dd, J=1.4, 7.7 Hz, 1H), 7.84–7.78 (m, 1H), 7.36–7.32 (m, 1H), 7.28 (s, 1H), 7.18–6.98 (m, 2H), 6.92 (dd, J=1.8, 8.0 Hz, 1H), 6.63 (s, 1H), 3.85 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[N:16]=[C:15]([CH:26]([F:28])[F:27])[CH:14]=2)=[CH:9][CH:8]=1)(=O)C>C1COCC1.CO>[F:28][CH:26]([F:27])[C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[CH:8][CH:9]=2)[N:17]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:16]=1
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCOC(C)=O)cc2)cn1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCO)cc2)cn1
Reaction time: 4 h
Yield: 33.7 %

Procedure:
To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyl}ethyl acetate (10 g) in THF (120 ml) and MeOH (30 ml) was added 1NNaOH (60 ml) at room temperature. The reaction mixture was stirred at the same temperature for 4 hrs, and then neutralized with 1NHCl (60 ml), evaporated, and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated to give crude product. The residue was column chromatographed on silica gel and crystalized from IPE and filtered to give 3.0 g of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol. The filtrate was evaporated and filtered to give 4.65 g of second crystal.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>C(#N)C>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18](=[O:19])[NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(NOCc1ccccc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under anhydrous conditions, 50 g of O-benzylhydroxylamine hydrochloride is suspended in 783 ml of acetonitrile. To the suspension is added 50.6 ml of pyridine followed by dropwise addition of 43.15 ml trichloroethyl chloroformate in 235 ml of acetonitrile. The reaction is allowed to stir overnight at room temperature. The mixture is concentrated in vacuo and diluted with ethyl acetate. The organic layer is washed with 0.5M citric acid,water, saturated sodium bicarbonate, saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation (bp 150° C. at 0.5 mm g.) to give 70 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[F:12][C:11]([F:13])([F:14])[C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(F)(F)F)cc1N
Temperature: 0 °C
Yield: 96.9 %

Procedure:
A solution of 2-nitro-4-trifluoromethylaniline (5.000 g, 24.26 mmol, Aldrich, used as received) and SnCl2.2 H2O (20.00 g, 88.64 mmol, Aldrich, used as received) in absolute ethanol (50 mL) was refluxed for 45 min. It was then poured into ice (85 g) and basified with 10% aq. NaHCO3 (250 mL). The resulting suspension was extracted with ethyl acetate (400 mL). The ethyl acetate extract was dried over Na2SO4 and evaporated to give 4.14 g (87%) of pure 4-trifluoromethyl-1,2-phenylenediamine as a red powder.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:15][CH:14]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33]C)=[O:31])[CH2:13][CH2:12]3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH3:36]>CN(C=O)C>[CH3:36][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:17]=2)[CH2:12][CH2:13][CH:14]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: CCOC(=O)CCCCCC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1C
Reaction time: 5 h

Procedure:
A suspension of sodium hydride (61.1 mg of a 60% mixture in mineral oil, 1.528 mmol) in dry DMF (5 ml) under N2 was treated with a solution of rac-ethyl 6-(6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexanoate (step 3) (131 mg, 0.306 mmol) in DMF (5 ml). After 30 mins at room temperature iodomethane (0.096 ml, 1.528 mmol) was added and stirring continued for 5 h. The mixture was partitioned between DCM (50 ml) and water (50 ml) and the aqueous portion was separated and extracted with DCM (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded a mixture of the title products as a colourless oil;
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:26][OH:27]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[N:26][OH:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: O=C(NCC(=O)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.2 %

Procedure:
To 2.8 g of N-[2-(3,5-dichloropyridin-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide in 19 ml of ethanol, 1.0 g of hydroxylamine hydrochloride was added, and the mixture was stirred at room temperature for 96 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 50 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 2.8 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1.[NH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1>O1CCCC1>[CH3:21][O:20][C:18]1[N:17]=[C:16]([O:22][CH3:23])[N:15]=[C:14]([NH:13][C:11]([NH:10][S:7]([C:3]2[C:2]([CH3:1])=[CH:6][S:5][CH:4]=2)(=[O:8])=[O:9])=[O:12])[N:19]=1
Reactant: Cc1cscc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(OC)n1
Solvent: C1CCOC1
Product: COc1nc(NC(=O)NS(=O)(=O)c2cscc2C)nc(OC)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
A solution of 2 g of 4-methyl-3-thiophenesulfonyl isocyanate was added to a suspension of 1.5 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 20 ml of tetrahydrofuran and the resulting mixture stirred for 16 hours at ambient temperature. The precipitate thus obtained was filtered off and recrystallized to yield 1.5 g of the desired product, m.p. 154°-156°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:15][NH:16][CH2:17][CH:13]3[CH2:12][O:11]2)=[CH:5][CH:4]=1.Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:31][C:28]1[CH:27]=[N:26][C:25]([N:16]2[CH2:17][CH:13]3[C:14]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)([N:10]([CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:11][CH2:12]3)[CH2:15]2)=[N:30][CH:29]=1
Reactant: COc1ccc(CN2OCC3CNCC32c2cccnc2)cc1
Reactant: Fc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(CN2OCC3CN(c4ncc(F)cn4)CC32c2cccnc2)cc1
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6a-(3-pyridyl)-3a,4,5,6-tetrahydro-3H-pyrrolo[3,4-c]isoxazole (1.33 g, 4.27 mmol) in 1,4-dioxane (30 mL) is added 2-chloro-5-fluoro-pyrimidine (2.55 g, 19.22 mmol) and diisopropylethylamine (3.72 mL, 21.36 mmol). The resulting solution is heated at 110° C. for 3 hours. The reaction is cooled and the solvent is evaporated under vacuum to give a residue. The residue is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.11 g, 54%). ES/MS (m/e): 408 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2].[CH3:38]I>>[C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([N:23]([CH3:38])[C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Reactant: CI
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[(3S)-3-(3-acetylphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: ESMS m/e: 513.2 (M+H)+.