Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Li+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:14][CH:15]1[CH2:19][CH:18]([C:20]([O:22]C)=[O:21])[NH:17][C:16]1=[O:24])[CH:8]=[CH:7]2.Cl>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([O:14][CH:15]([C:16]([OH:24])=[O:1])[CH2:19][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:17])[CH:8]=[CH:7]2
Reactant: [OH-]
Reactant: COC(=O)C1CC(Oc2ccc3cc(Br)ccc3c2)C(=O)N1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc2cc(Br)ccc2c1)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of lithium hydroxide (0.156 g) in water (2.0 ml) and tetrahydrofuran (6.6 ml) was treated with methyl 3-(6-bromo-2-naphthyloxy)-2-pyrrolidone-5-carboxylate (0.615 g), and heated to 60° C. After about 3.0 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (1.30 ml). The insolubles were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (5 ml). The insolubles were dried overnight in at vacuum oven at 60° C. to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:25]=1[NH2:26])([CH3:23])[CH3:22]>>[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[NH:26][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[C:19]([CH3:20])[C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:13])([CH3:33])[CH3:32]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1cc2c(cc1C)C(C(=O)O)c1ccccc1CO2
Product: Cc1cc2c(cc1C)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Yield: 93.4 %

Procedure:
The similar procedures as in Example 1 were repeated except using 0.84 g of 6,11-dihydro-2, 3-dimethyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 63 (Compound AB) in place of Compound A and 0.83 g of 2,6-diisopropylaniline in place of aniline to obtain 1.25 g of Compound 48.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:9]=[C:10](Cl)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of combined batches of methyl 3-amino-5-chloro-2-nitrobenzoate (39 g), morpholine (29.5 g) and K2CO3 (47 g) was stirred in DMF (200 ml) at 110° C. for 5 h. The mixture was cooled to room temperature and poured into water (1 L). It was extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo to afford the desired product as a yellow solid (22 g, yield 46%). 1H NMR (300 MHz, CDCl3): δ ppm 3.31 (t, 4H, J=4.8 Hz), 3.82 (t, 4H, J=4.8 Hz), 3.89 (s, 3H), 6.03 (d, 1H, J=2.4 Hz), 6.34 (d, 1H, J=2.4 Hz); LC-MS: m/e=282 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:49][C:50]1[CH:69]=[CH:68][C:53]([O:54][C:55]2[S:59][C:58]([NH2:60])=[N:57][C:56]=2[C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)=[CH:52][CH:51]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]([C:13](=[O:15])[NH:60][C:58]1[S:59][C:55]([O:54][C:53]2[CH:68]=[CH:69][C:50]([F:49])=[CH:51][CH:52]=2)=[C:56]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)[N:57]=1)([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyloxycarbonylamino-2-methyl-propionic acid (10.5 g, 44.2 mmol), HBTU (16.8 g, 44.3 mmol) and Et3N (6.2 mL, 45 mmol) in DMF (50 mL) was stirred at room temperature for 2 h. To this was added a solution of 5-(4-Fluoro-phenoxy)-4-(4-fluoro-phenyl)-thiazol-2-ylamine (9.62 g, ca. 32 mmol with some impurities present) in DMF (50 mL). The mixture was heated at 85° C. for 18 h and partitioned between EtOAc and, sequentially, 3M HCl and aqueous KOH. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 524.2 (MH+).
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[C:30]([O:31][C:32](=[O:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[Br:37]Br>ClCCCl>[Br:37][C:8]1[O:9][C:10]2[C:30]([O:31][C:32](=[O:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: COc1cc(C(=O)c2c([Si](C)(C)C(C)(C)C)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: BrBr
Solvent: ClCCCl
Product: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 43.2 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (120 mg, 0.44 mmol) in 1,2-dichloroethane (1 mL) at room temperature under nitrogen was added bromine (12 μl, 0.44 mmol) dropwise and the reaction mixture was stirred at this temperature for 10 minutes. After this time the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (20 mL), dried over magnesium sulfate and the solvent removed by distillation under vacuum. The crude product was purified by silica gel column chromatography (eluent=Hexane:diethyl ether; 8:2-7:3) to afford the title compound as a colourless crystalline solid (91 mg, 81%); 1H NMR (300 MHz, CDCl3) δ 7.40 (d, 1H, J=8.70 Hz), 7.14 (s, 2H, benzoyl-Hs), 6.98 (d, 1H, J=8.75 Hz), 3.94 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.86 (s, 6H, 2×OMe), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 187.95 (CO), 167.71, 152.75, 149.54, 147.49, 142.59, 131.92, 131.80, 123.91, 121.84, 119.89, 117.72, 109.89, 106.92, 60.69, 56.61, 56.00, 20.09.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](OC)(OC)([O:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([O:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CCCCC(OC)(OC)OC
Product: CCCCC(OC)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthovalerate
Reaction SMILES: [F:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl.[N:23]1([CH2:29][CH:30]([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[C:3]([C:12]([N:26]2[CH2:25][CH2:24][N:23]([CH2:29][CH:30]([N:34]3[CH:38]=[C:37]([C:39]4[C:40]5[CH:47]=[CH:46][NH:45][C:41]=5[N:42]=[CH:43][N:44]=4)[CH:36]=[N:35]3)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27]2)=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CCC(CN1CCN(C(=O)c2ncc(C(F)(F)F)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
N,N,N′,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0000426 mol) was added to a solution of 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (11 mg, 0.053 mmol) and triethylamine (30 microL, 0.21 mmol) in THF (0.4 mL). After stirring for 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (21 mg, 0.035 mmol; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (9 mg, 48%). 1H NMR (300 MHz, d6-dmso): δ □8.88 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.48 (dd, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.99 (tt, 1H), 3.67-3.56 (m, 2H), 3.25-3.12 (m, 4H), 2.92-2.79 (m, 2H), 2.66-2.55 (m, 1H), 2.55-2.38 (m 2H), 2.38-2.25 (m, 1H); LCMS (M+H)+: 528.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:13][CH:14]([OH:23])[CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(O)cc1OC
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(OCC(O)CCc2cccnc2)cc1OC
Yield: 6.6 %

Procedure:
Prepared according to the method described in Example 24b) from 3,4-dimethoxyphenol (0.77 g), (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g) and sodium hydroxide (0.2 g) in ethanol (45 ml) and water (5 ml) with heating at reflux for 1 hour. After work up the residue was purified by column chromatography over silica eluting with hexane:acetone (2:1) to give the title compound as a colourless oil (0.10 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Fc1cc(F)c2c(c1)NCC2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(F)cc(F)cc21
Yield: 59.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 310 mg of 4,6-difluoro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 225 mg of 2-[2-(4,6-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Cn1ccc(N)n1
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2ccn(C)n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 62.8 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 79 mg of 3-amino-1-methylpyrazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 134 mg of 1,6-dimethyl-4-hydroxy-N-(1-methylpyrazol-3-yl)-2-oxo-1,2-d ihydropyridine-3-carboxamide (hereinafter, referred to as present compound 25) represented by the formula:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15]Cl)[CH:12]=[CH:11][N:10]=2)[CH:4]=1.C([O:19][P:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])C>C(Cl)Cl.CCCCCC>[CH3:23][CH2:22][O:21][P:20]([O:24][CH2:25][CH3:26])([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15][P:20]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:19])[CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: ClCc1ccnc(-c2cc(CCl)ccn2)c1
Reactant: CCOP(OCC)OCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccnc(-c2cc(CP(=O)(OCC)OCC)ccn2)c1)OCC

Procedure:
Compound 5 (2.6 g, 10.3 mmol) was refluxed overnight under N2 in triethylphosphite (50 ml). Excess P(OEt)3 was evaporated and the resulting brown oil was column chromatographed (Al2O3, CH2Cl2/MeOH: 98/2). The yellow oil thus obtained was dissolved in a mixture of CH2Cl2/hexane (1/50 ml) and let stand in the freezer to afford after filtration 4 g (85%) of compound 6 as a slightly yellow crystalline solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)#[N:21].N(C(OCC)=O)=NC(O[CH2:34][CH3:35])=O>C1COCC1.CCOC(C)=O>[C:14]1([CH:34]([O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[CH3:35])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Oc1ccc(C#N)cc1)c1ccccc1

Procedure:
Add triphenylphosphine (7.869 g, 30 mmol) to a solution of sec-phenylethyl alcohol (1.467 g, 12 mmol), 4-cyanophenol (1.191 g, 10 mmol) and diethyl azodicarboxylate (4.528 g, 26 mmol) in anhydrous THF (50 mL) at 0° C. Stir the reaction at ambient temperature for 12 h. Dilute with EtOAc, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:8) to give (±)-4-(1-phenylethoxy)-benzonitrile with a small amount of triphenylphosphine (2.49 g total).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[CH2:22]([CH2:24][NH2:25])[OH:23]>O1CCOCC1>[OH:23][CH2:22][CH2:24][NH:25][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: NCCO
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: C1COCCO1
Product: N#Cc1nnc(NCCO)nc1N1CCc2ccccc2CC1

Procedure:
In analogy to the procedure as described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was reacted with ethanolamine in dioxane at 140° C. overnight to give 3-(2-hydroxy-ethylamino)-5 -(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a light yellow solid; MS: 311 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:25]1[CH:26]=[C:27]([CH2:34][OH:35])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]>C(#N)C>[OH:35][CH2:34][C:27]1[CH:28]=[CH:29][C:30]([N+:31]([O-:33])=[O:32])=[C:25]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (7.09 g, 32.1 mmol) and DIPEA (15 mL, 88 mmol) in ACN (50 mL) was added (3-fluoro-4-nitrophenyl)methanol (5 g, 29.2 mmol). The reaction was stirred overnight at 80° C. The reaction mixture was concentrated, loaded onto a silica-gel pre column, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-4-(5-(hydroxymethyl)-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide as an orange foam (7.0 g, 71.4% yield). MS, m/z (C17H25N3O4): calcd, 335.2. found, 336.0 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH2:23])[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:14])=[O:13].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:19][C@@H:18]2[C@@H:20]([NH:23][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:21][CH2:22][C@@H:17]2[CH2:16]1)(=[O:13])=[O:14]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Cl)C[C@@H]21
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1Cl)N1C[C@H]2CC[C@H](Nc3ccc(C(F)(F)F)cn3)[C@H]2C1
Temperature: 86 °C

Procedure:
(3aR,4S,6aS)-2-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}octahydrocyclopenta[c]pyrrol-4-amine (70 mg, 0.190 mmol) from Step B of Example 284, 2-bromo-5-(trifluoromethyl)pyridine (42.9 mg, 0.190 mmol), and triethylamine (0.079 mL, 0.569 mmol) were combined in ethanol (0.6 mL). The reaction was heated at 86° C. for 5 days and the solvent was evaporated in vacuo. The resultant material was purified using a 12 g silica gel cartridge with a gradient of 0-0.8% methanol (2 N ammonia)/dichloromethane over 20 minutes to give crude product. It was further purified by loading it onto 2×0.25 mm preparative thin-layer chromatography plate and eluted with 30% acetone/hexanes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.50-8.52 (bs, 1H), 8.40 (d, J=8.2 Hz, 1H), 8.03 (s, 1H), 7.96-7.98 (m, 1H), 7.75-7.78 (m, 1H), 7.54-7.59 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 4.30-4.42 (m, 1H), 3.89 (dd, J=10.2, 2.7 Hz, 1H), 3.57 (dd, J=10.2, 7.0 Hz, 1H), 3.43 (dd, J=9.9, 6.7 Hz, 1H), 3.39 (dd, J=10.0, 2.9 Hz, 1H), 2.68 (d, J=3.5 Hz, 2H), 2.13-2.20 (m, 1H), 1.90-1.97 (m, 1H), 1.59-1.66 (m, 1H), 1.40-1.48 (m, 1H); MS (ESI+) m/z 514 (M+H)+.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH2:16][O:17][CH2:18][CH:19]=[CH2:20])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26](Cl)=[O:27].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH2:18]([O:17][CH2:16][C:9]1[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([CH3:22])[CH:24]=1)=[O:21])[CH:19]=[CH2:20]
Reactant: C=CCOCc1c(OC)cccc1C(=O)NNC(C)(C)C
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: C=CCOCc1c(OC)cccc1C(=O)NN(C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
To a flask containing 2.0 g (0.0068 mol) of 2-allyloxymethyl-3-methoxy-benzoic acid N′-tert-butyl-hydrazide dissolved in 15 mL of CH2Cl2, was added 1.27 g (0.0075 mol) of 3,5-dimethylbenzoyl chloride in 10 mL of CH2Cl2 and 2.84 g of K2CO3 (0.02 mol) in 30 mL of H2O. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted and partitioned, and the organic phase was dried and solvent was removed in vacuio. The product was purified by silica gel chromatography; eluting in 25% ethyl acetate:hexane fractions, to yield 2.40 g of pure 3,5-dimethyl-benzoic acid N′-(2-allyloxymethyl-3-methoxy-benzoyl)-N-tert-butyl-hydrazide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.2 (t, 1H) 7.1 (s, 1H), 7.05 (d, 2H), 6.95 (m, 2H), 5.9 (m, 1H), 5.2-5.3 (q, 2H), 4.5 (d, 2H), 3.9 (m, 2H), 3.80 (s, 3H), 2.245 (s, 6H), 1.547 (s, 9H).
Reaction SMILES: C1C2C(COC(=O)[N:17]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:59])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([N:36]4[C:39](=[O:40])[CH:38]([CH2:41][CH2:42][CH:43]([OH:50])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:37]4[C:51]4[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=4)=[CH:32][CH:31]=3)C3C=CC=CC=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>CN(C)C=O>[OH:50][CH:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:42][CH2:41][CH:38]1[C:39](=[O:40])[N:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:28](=[O:59])[CH2:27][CH2:26][CH2:25][CH2:24][NH2:17])=[CH:35][CH:34]=2)[CH:37]1[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN(C(=O)OCC3c4ccccc4-c4ccccc43)c3ccccc3)cc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccccc3)C(=O)N2c2ccc(NC(=O)CCCCN)cc2)cc1

Procedure:
570 mg (0.78 mmol) of product 8 and 0.8 ml of diethylamin are solved in 5 ml of DMF (dimethylformamid). It is evaporated after 1 h at room temperature. The residue is purified by flash chromatography (methylenchloride/methanol/conc. ammoniac 30:10:3) 220 mg (56%) of product 9 is obtained in form of an amorphic solid compound: C30H35N3O4 (501.63) MS (ESI+) 502.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:19]([NH:21][CH3:22])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C=O.[CH:25](O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH:19]([N:21]([CH3:25])[CH3:22])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=CO
Agent: C=O
Solvent: CO
Product: CC(C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1)N(C)C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a solution of 47 (200 mg, 0.60 mmol) in MeOH (5 mL) was added HCHO (35 mg, 37%, 1.20 mml), HCO2H (0.3 mL) and NaB(CN)H3 (75 mg, 1.20 mmol). The reaction mixture was stirred for 20 min before being concentrated. The residue was dissolved in MeOH (2 mL) and subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give 48 (188 mg, 91%). 1H NMR (400 MHz, CDCl3)δ 7.34 (d, J=8.4 Hz, 1 H), 7.25 (m, 2 H), 7.20 (m, 2 H) 7.12 (m, 2 H), 7.0 (dd, J=2.0, 8.4 Hz, 1 H), 6.83 (d, J=7.6Hz, 1 H), 6.40 (s, 1 H), 4.10 (t, J=8.4 Hz, 1 H), 2.65 (d, t, J=6.4, 13.2 Hz, 1 H), 2.65 (dd, J=6.8, 16.4 Hz, 1 H), 2.54 (dd, J=9.2, 16.4 Hz, 1 H), 2.21 (s, 6 H), 1.01 (d, J=6.8 Hz, 1 H); 13C NMR (100 m Hz, CDCl3)δ 144.87, 142.04, 136.44, 134.67, 132.42, 130.61, 130.45, 128.16, 127.78, 127.53, 177.43, 126.61, 124.19, 124.12, 67.03, 43.72, 43.83, 43.50, 32.36, 16.45; ESI MS m/z 346.1