Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][CH2:9][P:10](=[O:21])([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:28]([O:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=1)=[O:33])=[O:29]>O1CCCC1.CCCCCC>[CH:1](=[N:8][CH:9]([P:10]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:21])[C:28]([O:30][CH2:31][C:32]([C:34]1[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=1)=[O:33])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCC(=O)c1ccc(Br)cc1
Reactant: CCCCOP(=O)(CN=Cc1ccccc1)OCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOP(=O)(OCCCC)C(N=Cc1ccccc1)C(=O)OCC(=O)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
Dibutyl N-benzylidene-aminomethylphosphonate (31.1 g) is dissolved in anhydrous tetrahydrofuran (500 ml) and the solution is cooled to -78° under a nitrogen atmosphere. Butyllithium (46 ml of a 2.2 M solution in hexane) is added over a period of 5 minutes. The resulting solution is stirred an additional 30 minutes at -78°, then treated dropwise over a period of 45 minutes with p-bromophenacyl chloroformate (13.9 g) in tetrahydrofuran (100 ml). The reaction mixture is stirred an additiona 2 hours at -78° followed by gradual warming to 3° over a period of 30 minutes. Evaporation of the solvent in vacuo leaves a gum which is partitioned between ether (500 ml) and 0.5 M pH 3 phosphate buffer (100 ml). The ethereal phase is separated, washed with water and saturated brine, dried over magnesium sulfate filtered, and evaporated in vacuo to an oil. Chromatographic purification of this material on silica gel gives p-bromophenacyl N-benzylidene-α-amino-dibutylphosphonoacetate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:14]OC1C=C(O)C=CC=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2([C:43]3[C:34](=[CH:35][C:36]4[O:41][CH2:40][CH2:39][O:38][C:37]=4[CH:42]=3)[O:33][CH2:32]2)[C:24]1=[O:44]>>[CH3:14][N:23]1[C:31]2[C:26](=[C:27]([O:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:8]=3)[CH:28]=[CH:29][CH:30]=2)[C:25]2([C:43]3[C:34](=[CH:35][C:36]4[O:41][CH2:40][CH2:39][O:38][C:37]=4[CH:42]=3)[O:33][CH2:32]2)[C:24]1=[O:44]
Reactant: Oc1cccc(N2CCOCC2)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COc1cccc(O)c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Oc3cccc(N4CCOCC4)c3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 16.79 and making non-critical variations using 3-morpholinophenol to replace 3-methoxyphenol, morpholin-4-ylphenoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (53%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.18-7.24 (m, 1H), 7.01-7.09 (m, 1H), 6.65 (d, J=7.7 Hz, 1H), 6.55 (d, J=8.5 Hz, 2H), 6.27 (s, 1H), 6.26-6.21 (m, 2H), 6.20 (s, 1H), 4.84 (ABq, 2H), 4.13-4.00 (m, 4H), 3.82-3.74 (m, 4H), 3.25 (s, 3H), 3.07-3.00 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.6, 157.5, 155.6, 153.3, 152.5, 144.8, 144.3, 137.6, 130.1, 129.7, 121.1, 119.4, 114.0, 111.0, 110.5, 109.7, 105.9, 103.6, 99.1, 77.6, 66.7, 64.4, 63.8, 57.3, 48.9, 27.0; MS (ES+) m/z 486.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[SH:13])([O-])=O.[NH2:14][C:15](N)=S>CN(C)C=O.O>[NH2:14][C:15]1[S:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(S)c([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1

Procedure:
A solution of 10 g of 2,4-dinitrothiophenol and 7.6 g of thiourea in 50 ml of dimethylformamide is heated at 120° C. for 3 hours. The mixture is diluted with 300 ml of water, and the solid is filtered off with suction and washed with water. 7.3 g of crude 2-amino-5-nitrobenzothiazole, the identity of which was confirmed by TLC comparison with authentic material, are obtained.
Reaction SMILES: C([O-])(=O)C.[O:5]=[C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:18])=[NH2+:17])[N:10]=[C:9]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=2)[CH:8]=[CH:7]1.[CH:31]([CH:33]([CH:39]=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.O>N1C=CC=CC=1>[O:5]=[C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:16]3[N:18]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:17]=3)[CH:19]=[CH:20][CH:21]=2)[N:10]=[C:9]([C:22]2[CH:23]=[C:24]([F:30])[C:25]([F:29])=[C:26]([F:28])[CH:27]=2)[CH:8]=[CH:7]1
Reactant: NC(=[NH2+])c1cccc(Cn2nc(-c3cc(F)c(F)c(F)c3)ccc2=O)c1
Reactant: CCOC(=O)C(C=O)C=O
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4.7 g (11.23 mmol) of 3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidinium acetate are suspended in 40 ml of pyridine, and 2.4 g (16.85 mmol) of ethyl 2-formyl-3-oxopropionate (prepared in accordance with S. H. Berz et al., Journal of Organic Chemistry 1982, 47, 2216) are added, and the mixture is stirred at 80° C. for 4 h. A further 500 mg (3.47 mmol) of ethyl 2-formyl-3-oxopropionate are subsequently added, and the mixture is stirred at 80° C. for 1 h. The reaction mixture is stirred into 400 ml of water, and the precipitate is filtered off with suction, washed a number of times with water and dried in a drying cabinet. Yield: 4.43 g of “A29” (76%), Rt=3.58 min (method B), ESI 467.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:12][C:4]1[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[CH3:11]
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1Cl
Product: Cc1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)nc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 34 from 2,6-dichloro-5-methyl-3-nitropyridine (Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59,190.) and 4-aminophenylethyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O[C:15](=O)[CH3:16])(=O)C.[N-:18]=[N+:19]=[N-:20].[Na+].Cl>[OH-].[Na+].C(O)(=O)C>[CH3:16][C:15]1[N:1]([C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[N:20]=[N:19][N:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nnnn1-c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-aminobenzoic acid (100.0 g, 0.73 mol) in acetic anhydride (400 ml, 4.2 mol) was heated to reflux for 2 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in glacial acetic acid (500 ml) and NaN3 (49.77 g, 0.77 mol) was added. The mixture was stirred overnight at room temperature followed by concentration of the acetic acid in vacuo. The residue was dissolved in 10% NaOH (500 ml) solution and heated to reflux for 3.5 hours. The reaction was cooled to room temperature and then poured over a mixture of ice water (2 L) and HCl (150 ml). A white solid precipitated and was collected by vacuum filtration. The solid was dried in vacuo to yield 130.5 g of 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([Cl:23])[C:16]([Cl:24])=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[C:25](OCC)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].[CH3:33][S:34]([OH:37])(=[O:36])=[O:35]>>[S:34]([OH:37])(=[O:36])(=[O:35])[CH3:33].[Cl:23][C:17]1[C:16]([Cl:24])=[C:15]2[C:14]3=[C:19]([C:20]4[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]=4[N:13]3[CH:27]([CH3:28])[CH2:26][C:25]2=[O:29])[CH:18]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Reactant: C/C=C/C(=O)OCC
Agent: CS(=O)(=O)O
Product: CC1CC(=O)c2c(Cl)c(Cl)cc3c4c(n1c23)CCNCC4

Procedure:
Following the general procedure of Example 41, making non-critical variations but starting with 3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, using ethyl crotonate in step 7, and using methanesulfonic acid for the salt formation, the title compound was obtained (mp 225-230° C. [dec.]). 1H NMR (d-DMSO) δ 8.94, 8.12, 4.97, 3.48-3.20, 3.13, 2.77, 2.30, 1.20; IR (drift) 3029, 2979, 2849, 2792, 1683, 1481, 1410, 1312, 1214, 1196, 1184, 1161, 1145,1040, 775 cm−1.
Reaction SMILES: C(OP([CH2:9][C:10](=[O:12])[CH3:11])(OCC)=O)C.[CH:13]([O:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[O:22])=[CH:19][C:18]=1[CH3:32])([CH3:15])[CH3:14]>O1CCCC1>[CH:13]([O:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([N:23]2[CH2:28][CH2:27][C:26](=[CH:9][C:10](=[O:12])[CH3:11])[CH2:25][CH2:24]2)=[O:22])=[CH:19][C:18]=1[CH3:32])([CH3:15])[CH3:14]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: Cc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Solvent: C1CCOC1
Product: CC(=O)C=C1CCN(C(=O)c2ccc(OC(C)C)c(C)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To an oven dried flask was placed 60% sodium hydride in mineral oil (1.5 g, 36 mmol). To the flask was added tetrahydrofuran (90 mL) under a nitrogen atmosphere. The mixture was cooled to 0° C. and a solution of 1-diethoxyphosphorylpropan-2-one (7.1 mL, 37 mmol) in tetrahydrofuran (20 mL) was added dropwise. The mixture was stirred at 25° C. for 30 min and treated with 1-(4-isopropoxy-3-methyl-benzoyl)piperidin-4-one (10 g, 36 mmol) in tetrahydrofuran (90 mL). The mixture was stirred at 25° C. for 24 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to afford 1-[1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidylidene]propan-2-one (10.2 g) 1H NMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 6.12 (s, 1H), 4.60-4.51 (m, 1H), 3.66 (br d, 4H), 2.95 (br s, 2H), 2.50-2.33 (m, 2H), 2.19 (s, 6H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 315.18, found 316.0 (M+1)+; Retention time: 2.2 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][NH:13][CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13]([C:25](=[O:26])[C:24]3[CH:28]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]=3[N:29]3[N:33]=[CH:32][CH:31]=[N:30]3)[CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1cc(OCC2CCCC(C)NC2)ccc1F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC(COc3ccc(F)c(C)c3)CCCC2C)c1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methylazepane (2-7, 50 mg, 0.20 mmol, 1.0 equiv) in DMF (3 mL) was treated with 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (45 mg, 0.22 mmol, 1.1 equiv), EDC (46 mg, 0.24 mmol, 1.2 equiv), HOBT (37 mg, 0.24 mmol, 1.2 equiv) and triethylamine (83 ul, 60 mg, 0.60 mmol, 3.0 equiv) and the resulting mixture was stirred at 23° C. for 16 hours. The mixture was filtered and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methyl-1-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]azepane (2-8). δ 7.95-6.14 (m, 8H), 4.97-0.65 (m, 21H). LRMS m/z (M+H) 437.4 found, 437.2 required.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19]2)=[CH:14][CH:13]=1.[NH2:26][CH2:27][CH2:28][OH:29].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:29][CH2:28][CH2:27][NH:26][C:23]([C:21]1[CH:20]=[N:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[CH3:2])=[CH:17][CH:16]=2)[CH:22]=1)=[O:24]
Reactant: NCCO
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)O)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO)cn2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxylic acid hydrochloride prepared in Example 2-(1) (1.00 g), 2-aminoethanol (0.400 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.580 g), 1-hydroxybenzotriazole monohydrate (0.460 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=18:1) to give the titled compound (0.920 g) as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:12](=O)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[OH2:14].[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:12]=1[CH2:17][C:16]([O:15][CH2:19][CH3:18])=[O:14]
Reactant: O=C1CCc2ccccc2C1
Reactant: C1CCOC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1=Cc2ccccc2CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of 56 g (0.25 mol) of triethyl phosphonoacetate in 70 ml of tetrahydrofuran (THF) is added dropwise to a suspension, maintained at 0° C., of 6 g (0.25 mol) of NaH in 600 ml of anhydrous THF under a nitrogen atmosphere. The mixture is then stirred at 10° C. for 30 minutes, cooled to 0° C., and then treated, dropwise, with a solution of 36.52 g (0.25 mol) of β-tetralone in 50 ml of anhydrous THF. After stirring for 3 hours at 20° C., the mixture is hydrolysed, at 0° C., with 200 ml of water. The solvent is evaporated off under reduced pressure and the residue is extracted with dichloromethane (CH2Cl2)(3×200 ml). The combined organic phases are washed with saturated NaCl solution, dried and concentrated to yield an oily brown residue. Distillation under a partial vacuum allows the title compound to be obtained in the form of a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.C(N(CC)CC)C.Cl.[CH:21]1([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:27]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:28][CH:29]2[CH2:31][CH2:30]2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: C1CCC(NCC2CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(N(CC2CC2)C2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 5.00 g; 24.1 mmol) in THF (50 mL) was treated triethylamine (7.38 ml; 53.1 mmol) and cyclohexyl(cyclopropylmethyl)amine hydrochloride (Chembridge, 4.58 g; 24.1 mmol. The reaction mixture was stirred for 2 days at RT. The solvent was evaporated under reduced pressure, the remaining residue was partitioned between 100 ml of ethyl acetate and a saturated aqueous solution of NH4Cl (50 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc to give the title product as a yellow oil, which solidified upon standing (6.14 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[C:22]([C:23](=[O:24])[NH2:25])=[CH:26][CH:27]=[CH:28][N:29]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: NC(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ncccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Dissolve [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (Example 377, Part A) (0.500 g, 2.11 mmol) in DMF (10.5 mL). Add NaH (80% in mineral oil) (0.070 g, 2.32 mmol). Stir at room temperature for 30 minutes. Add 2-chloronicotinamide (0.330 g, 2.11 mmol) and heat to 100° C. Remove DMF as an azeotrope with xylenes after 18¾ hours. Take the solid up with ethyl acetate (150 mL) and 1.0 N NaOH (75 mL). Separate the two layers. Extract the aqueous layer with ethyl acetate (1×150 mL). Wash the combined organic layers with brine (1×50 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 35-45% ethyl acetate in dichloromethane to give the title compound (0.538 g, 71.4%): MS ES+ 358.3 (M+H)+, base peak ES+ 302.1 (M+2H—C(CH3)3)+, MS ES− 356.4 (M−H)−; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=12.9 min, 100% purity.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:15])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](Cl)=[C:26](Cl)[CH:25]=2)[CH2:19]1.NCC1CCN(CC2C=CC=CC=2)C1>>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:18]([CH2:17][NH:16][C:13](=[O:15])[CH2:12][N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH2:19]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)Cn1ccc(-c2ccccc2)n1
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Agent: NCC1CCN(Cc2ccccc2)C1
Product: O=C(Cn1ccc(-c2ccccc2)n1)NCC1CCN(Cc2ccccc2)C1

Procedure:
Proceeding as described above but substituting 4-(2,5-dimethylphenyl)-4-oxobutyric acid with 2-(3-phenylpyrazol-1-yl)acetic acid and 3-aminomethyl-1-(3,4-dichlorobenzyl)pyrrolidine with 3-aminomethyl-1-benzylpyrrolidine gave N-[1-(benzyl)-pyrrolidin-3-(RS)-ylmethyl]-2-(3-phenylpyrazol-1-yl)acetamide.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](OCC)=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(C)(C)C.C1COCC1>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:3][C:2]([NH2:4])=[NH:1])=[O:36])=[CH:27][CH:26]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC(=N)N)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.8 %

Procedure:
A solution of 3.64 g (61.69 mmol) of guanidine in 150 ml of tert-butanol was added to a solution of 20 g (41.23 mmol) of (1.1) in THF and the mixture was stirred at room temperature for 18 h. A further 4.5 g of guanidine in 150 ml of tert-butanol were then added, and the reaction solution was stirred at room temperature for 7 h, concentrated to about a half and stirred at room temperature for a further 18 h. The solvent was removed in vacuo and the residue was first filtered through basic Al2O3 using CH2Cl2/MeOH/H2O (95/5/0.5) and then chromatographed on silica gel by means of MPLC using CH2Cl2/MeOH/acetic acid (90/10/0.5). 8.6 g (42%) of (1.2) were obtained.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([NH:36][NH2:37])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:17]([O:24][N:25]1[C:31](=[O:32])[N:30]2[CH2:33][C@H:26]1[CH2:27][CH2:28][C@H:29]2[C:34]([N:36]([C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:8])[NH2:37])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: NN(C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
Morpholine-4-carbonyl chloride (297 mg, 1.99 mmol) was added dropwise over a period of 10 minutes to a solution of DMAP (24 mg, 0.199 mmol) and pyridine (0.16 mL, 1.99 mmol) in dry DCM (5 mL). The mixture was stirred at 0° C. for 20 minutes then, a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide hydrochloride (0.65 g, 1.99 mmol) in dry DCM (2.0 mL) was added over a period of 10 minutes. The mixture was stirred at 0° C. for 15 min and was then allowed to warm to rt and was stirred overnight. The reaction mixture was diluted with DCM (10 mL), and washed with 1N HCl (10 mL), and saturated sodium chloride (10 mL), then was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (0 to 1:100 MeOH/DCM, containing 1% TEA) to give N-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl) morpholine-4-carbohydrazide (0.38 g, 47%) as a white solid. ESI-MS (EI+, m/z): 404.19 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[Cl:25])[CH2:9][CH2:8][CH2:7]1)=[O:4].[C:27](=O)([O-])[O-].[Na+].[Na+].C(O[CH2:37][CH3:38])(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:27][CH2:37][CH3:38])=[CH:20][C:19]=2[Cl:25])[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(N)cc2Cl)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCNc1ccc(C(=O)N2CCCC(CC(=O)OC)c3ccccc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 5-methoxycarbonylmethyl-1-(4-amino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (50 g), n-iodopropane (130 ml) and sodium carbonate (185 g) in dimethylformamide (1.0 liter) is stirred overnight at 60° C. To the mixture is added ethyl acetate, and the mixture is washed with water, dried, concentrated, and purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1) to give 5-methoxycarbonylmethyl-1-(4-n-propylamino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (30 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:20])([CH3:21])[CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)CO)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Yield: 78.1 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-2 using ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido)methyl)benzoate (712 mg, 2.15 mmol) in THF:MeOH:H2O (2:1:1; 8 mL) and NaOH (344 mg, 8.60 mmol) to afford 510 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 8.08-8.05 (t, J=8.0 Hz, 1H), 7.36-7.33 (m, 2H), 4.90 (t, 1H), 4.29-4.28 (d, J=6.0 Hz, 2H), 3.38 (m, 2H), 1.06 (s, 6H).