Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:25]([F:29])[C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:25]([F:29])[C:26]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: NC1CC1
Reactant: COc1ccc(Cl)cc1-c1nn(C(F)C(=O)O)cc1NC(=O)c1cnn2cccnc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(F)C(=O)NC2CC2)cc1NC(=O)c1cnn2cccnc12
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)-2-fluoroacetic acid (39.1 mg, 0.088 mmol) and cyclopropylamine (10 mg, 0.18 mmol) in 1.0 mL DMF was added (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (91 mg, 0.18 mmol) and the mixture stirred for 1 h. The crude mixture was purified by reverse phase HPLC and lyophilized to give 9.1 mg (21%) of N-(3-(5-chloro-2-methoxyphenyl)-1-(2-(cyclopropylamino)-1-fluoro-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a colorless solid. LCMS (ESI) m+H=484.1. 1H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 9.34 (dd, J=7.0, 1.4 Hz, 1H), 8.83 (d, J=4.4 Hz, 1H), 8.76 (dd, J=4.2, 1.5 Hz, 1H), 8.68 (s, 1H), 8.55 (s, 1H), 7.58 (dd, J=8.9, 2.7 Hz, 1H), 7.37 (t, J=5.7 Hz, 2H), 7.29 (dd, J=7.0, 4.2 Hz, 1H), 6.80 (d, J=50.7 Hz, 1H), 3.85 (s, 3H), 2.82 (dd, J=7.3, 3.3 Hz, 1H), 0.70 (t, J=7.0 Hz, 2H), 0.64-0.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][CH:8]=[C:7](O)[C:6]=2[CH:15]=1.[CH3:16][NH:17][CH3:18]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][CH:8]=[C:7]([N:17]([CH3:18])[CH3:16])[C:6]=2[CH:15]=1
Reactant: O=S1(=O)CCC=C(O)c2cc(Cl)ccc21
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)C1=CCCS(=O)(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the stirred suspension of 1.09 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1,1-dioxide in 20 ml of benzene the solution of 0.5 g of titanium tetrachloride in 10 ml of benzene is added dropwise while cooling with ice, and the mixture stirred for 1/2 hour at 0°. Thereupon the solution of 0.7 g of dimethylamine in 10 ml f benzene is added dropwise and the mixture allowed to warm up to room temperature. It is filtered, the filtrate evaporated, and the residue recrystallized from diethyl ether, to yield the 7-chloro-5-dimethylamino-2,3-dihydro-1-benzothiepin-1,1-dioxide melting at 93°-95°.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3ccc(Cl)cc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(4-chlorobenzoyl)-5-methoxybenzoic acid unpurified with hydrazine hydrate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1.O>[N:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=5)=[O:19])=[CH:13][CH:12]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1ccc(-c2cnc3cc(Cl)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1)Nc1cccc(C(F)(F)F)c1
Yield: 22.5 %

Procedure:
Load in a 5 mL septum capped vial the following: small magnetic stir bar, 1-[4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (250 mg, 0.58 mmol), 4-pyridyl boronic acid (77.4 mg, 0.63 mmols, 1.1 Eq), S-phos (236 mg), Pd(OAc)2 (60 mg), K3PO4 (237 mg, 1.12 mmol), 1,4-dioxane: H2O 2:1. Heat the reaction to 50° C. for 24 hours, cool and purify with a Varian SCX® (10 g) column that is pre-washed with water and methanol, and elute the product with 2 N NH3 in methanol. Evaporate the product containing fractions under reduced pressure and take up into CH2Cl2 and chromatograph using SiO2 eluting with a gradient of 0% to 10% of 2 M NH3 in MeOH with the balance CH2Cl2. Evaporate the fractions containing the product under reduced pressure, then vacuum oven dry at 40° C. to give the title compound as a yellow solid 61.8 mg (22.5%). MS (ES), m/z 474 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([O:43]CC3C=CC([N+]([O-])=O)=CC=3)=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30]([N:32]4[CH2:35][CH:34]([N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)[CH2:33]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([OH:43])=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][NH:15][C@H:14]([C:30]([N:32]4[CH2:33][CH:34]([N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)[CH2:35]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(n5ccnc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(n5ccnc5)C4)C3)[C@H](C)[C@H]12

Procedure:
0.25 g of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[3-(1-imidazolyl)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] was dissolved in a mixture of 7.5 ml of tetrahydrofuran and 7.5 ml of water, and 0.25 g of a 10% w/w palladium-on-carbon catalyst was added to the resulting solution, after which the mixture was hydrogenated at room temperture for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration and the filtrate was washed with diethyl ether. The resulting aqueous layer was then concentrated by evaporation under reduced pressure, and the residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, 30 g, manufactured by Nacalai Tesque). Of the fractions obtained by elution with 7% by volume aqueous acetonitrile, the fraction containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to obtain 70 mg of the title compound as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13]([OH:17])(=[O:16])[CH:14]=O>>[OH:12][C:10]1([CH3:11])[O:17][C:13](=[O:16])[CH:14]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: O=CC(=O)O
Product: COc1ccc(C2=CC(=O)OC2(C)O)cc1

Procedure:
16.42 g (0.10 mol) of 4-methoxyphenylacetone and an aqueous solution of 45% glyoxylic acid (19.4 ml, 0.11 mol) were stirred overnight at 100° C. The reaction liquid was concentrated under reduced pressure to obtain a crude product of 5-hydroxy-4-(4-methoxyphenyl)-5-methyl-5H-furan-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Li+].[B-](CC)(CC)CC>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)cc1N

Procedure:
Methyl 2-amino-4-carbomethoxybenzoate (12, 4.0 g, 19.0 mmol) was dissolved in dry THF and cooled in a dry ice-acetone bath under an inert atmosphere. Super-hydride (65 mL, 1.0M) was added slowly by syringe over a period of 1 h. A small aliquot of the solution was quenched with water and purified on a silica gel column to yield methyl 2-amino-4-hydroxymethylbenzoate as a white solid: mp. 100°- 102° C. 1H NMR (CDCl3) δ 3.82 (s, 3 H, CH3), 4.64 (s, 2 H, CH2), 5.82 (br s, 2 H, NH2), 6.58 (d, J=8.1 Hz, 1 H), 6.66 (br s, 1 H), 7.81 (d, J=8.0 Hz, 1 H); MS (CI/NH3) m/e 182 (MH+, base), 167, 150.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH2:8]Br)[CH:7]=1.[OH:13][CH2:14][C:15]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:10][CH3:11])=[C:6]([CH:7]=1)[CH2:8][O:13][CH2:14][C:15]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: COc1c(C)cc(Br)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)cc(Br)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Bromo-1-(bromomethyl)-2-methoxy-3-methylbenzene (0.88 g, 3.0 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.79 g, 2.7 mmol) were combined in dimethylformamide (9 mL) and cooled to 0° C. The reaction was treated with sodium hydride (144 mg, 5.99 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 1.24 g (82%). 1H-NMR (CDCl3, 500 MHz) δ 7.34-7.35 (m, 4H), 7.21-7.24 (m, 1H), 7.19-7.20 (m, 1H), 7.10 (m, 1H), 4.34 (s, 2H), 3.72-3.76 (m, 2H), 3.53 (s, 3H), 3.43 (s, 2H), 3.01-3.07 (m, 2H), 2.21 (s, 3H), 2.17-2.19 (m, 2H), 1.85-1.91 (m, 2H), 1.43 (s, 9H). Mass spec.: 506.45 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]1)[CH3:4]>C1COCC1.[Pd]>[NH2:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][OH:1])=[O:16])[CH:12]=1
Reactant: C[C@@H](CO)NC(=O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@@H](CO)NC(=O)Cn1cc(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A mixture of N—((S)-1-hydroxypropan-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide (4 g, 17.5 mmol) and 10% Pd/C (500 mg) in THF (50 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The Pd/C was removed through filtration and the filtrate was concentrated in vacuo to afford (S)-2-(4-amino-1H-pyrazol-1-yl)-N-(1-hydroxypropan-2-yl)acetamide V-1 (3.5 g, 100%) as a grey solid which was used without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:33]=[CH:32][C:26]3[C:27](=[O:31])[CH2:28][CH2:29][O:30][C:25]=3[C:24]=2[CH2:34][CH2:35][CH3:36])[C:11]=1[CH2:37][CH2:38][C:39]([OH:41])=[O:40])([OH:3])=[O:2].[OH-].[Na+:43]>O>[Na+:43].[Na+:43].[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:33]=[CH:32][C:26]3[C:27](=[O:31])[CH2:28][CH2:29][O:30][C:25]=3[C:24]=2[CH2:34][CH2:35][CH3:36])[C:11]=1[CH2:37][CH2:38][C:39]([O-:41])=[O:40])([OH:3])=[O:2].[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:33]=[CH:32][C:26]3[C:27](=[O:31])[CH2:28][CH2:29][O:30][C:25]=3[C:24]=2[CH2:34][CH2:35][CH3:36])[C:11]=1[CH2:37][CH2:38][C:39]([O-:41])=[O:40])([OH:3])=[O:2]
Reactant: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)O)c2CCC(=O)[O-])ccc2c1OCCC2=O

Procedure:
The dicarboxylic acid from example 157 (10 mmol) was neutralized with 20 mL (20 mmol) of 1N aqueous sodium hydroxide. The resulting mixture was diluted with more water and the solution was freeze-dried giving the title salt.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: ClCCN1CCCC1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=569.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)pyrrolidine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([C:13]([O-:15])=[O:14])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](O)(=O)[CH3:17]>[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(C(=O)[O-])N1
Reactant: CC(=O)O
Agent: [Zn]
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)N1

Procedure:
53.5 g of Diazald® in 750 ml of tert.-butyl methyl ether are cooled to 0° C., and 16.5 g of KOH dissolved in 250 ml of ethanol/water (9:1) are added. The mixture is warmed to room temperature and stirred at room temperature for 1 h. 25.0 g (0.25 mol) ethyl acrylate in 20 ml of tert.-butyl methyl ether are added dropwise over 1.5 h, with 40 ml of water being added towards the end. For the working up, 800 ml of diethyl ether are added, and the organic phase is separated off, washed with saturated NaCl solution and dried over Na2SO4. The residue is dissolved in 500 ml of DMF, and 55 ml of triethylamine, 100 mg of N,N-dimethylaminopyridine and 54 g (0.25 mol) of di-tert.-butyl pyrocarbonate are added. Chromatography on silica gel results in 8 g of ethyl Δ2 -1-tert.-butoxycarbonylpyrazoline-3-carboxylate. 6 g of the pyrazoline derivatives are dissolved in 100 ml of acetic acid, and 7 g of zinc powder are added and stirred. The reaction solution is removed by filtration after 2 h, the filtrate is evaporated in a rotary evaporator, and the residue is chromatographed on silica gel. 4.5 g of ethyl 1-tert.-butoxycarbonylpyrazolidine-3-carboxylate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NN1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 78 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (81 mg, 78%) which was obtained as a white solid. MS: m/e=413.3 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([N:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:14]=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:27]O>CN(C=O)C>[NH2:1][CH:2]([CH:6]([N:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:14]=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:27])=[O:4]
Reactant: NC(C(=O)O)C(c1ccccc1)N(C=O)Cc1ccccc1
Reactant: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)C(c1ccccc1)N(C=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
13.5 g (0.04 mol) of 2-amino-3-(N-benzyl-N-formylamino)-3-phenylpropionic acid were dissolved in methanol, and 7.1 g (0.06 mol) of thionyl chloride and 1 drop of DMF were added dropwise. After 20 hours, the solvents were removed, the residue was suspended in diethyl ether and 5% strength NaHCO3 solution was added with stirring. The ether phase was separated off, washed and dried. Removal of the solvents gave 4.0 g of the title compound as a colorless oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[C:4]([NH2:6])=[O:5])[CH3:2].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]=O>>[CH2:1]([N:3]1[C:7]2[C:12](=[CH:11][C:10]3[O:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCN(C(N)=O)c1ccc2c(c1)OCO2
Product: CCN1C(=O)NC(c2ccc3ccccc3c2)c2cc3c(cc21)OCO3
Yield: 46 %

Procedure:
This compound was synthesized from N-ethyl-N-[3,4-(methylenedioxy)phenyl]urea (247 mg) and 2-naphthaldehyde (182 mg) by the procedure described in example 10 in 46% yield, mp: 193-195° C. 1H NMR (CDCl3): 7.86-7.82 (m, 2H), 7.74 (s, 1H), 7.52-7.42 (m, 4H), 6.57 (s, 1H), 6.30 (s, 1H), 5.90 (s, 1H), 5.87 (s, 1H), 5.61 (s, 1H), 5.18 (s, 1H), 3.97 (q, J=6.6, 2H), 1.32 (t, J=6.6, 3H). Anal. calcd. for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C, 72.53; H, 4.95; N, 7.54.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[C:10]([O:14]C)=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.B(Cl)(Cl)[Cl:25].CO>ClCCCl>[ClH:25].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([OH:16])[C:10]([OH:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1
Reactant: ClB(Cl)Cl
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Agent: Cl
Solvent: CO
Solvent: ClCCCl
Product: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A slurry of 10 g (25 mmol) of 1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, from Step 2, in 150 mL of 1,2-dichloroethane was cooled to 10° C. under a nitrogen atmosphere. Boron trichloride was passed through the reaction mixture until 27 g (230 mmol) had been added. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was then cooled in ice and 100 mL of methanol was added dropwise. The reaction mixture was again allowed to warm to ambient temperature and concentrated in vacuo. Twice, 500 mL portions of methanol were added to the residue and it was reconcentrated. The resultant foam was dissolved in 40 mL of ethanol, filtered and the solution was treated with 40 mL of methylene chloride and 80 mL of heptane. Off-white crystals of 1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene hydrochloride (5.1 g, 56% yield) were collected by filtration, m.p. 204°-205° C. The 1H NMR spectrum was identical to the spectrum for the product of Example 2A.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[F:31][C:32]([F:44])([F:43])[S:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1.CO.ClCCl>O1CCCC1>[CH2:24]([O:23][C@@H:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([S:33][C:32]([F:43])([F:31])[F:44])=[CH:35][CH:36]=3)=[O:42])=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])[CH3:25]
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)Nc3ccc(SC(F)(F)F)cc3)cc2)cc1)C(=O)O
Yield: 57 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; (0.547 mmole) was dissolved in tetrahydrofuran (5 ml). Sodium hydrogencarbonate (0.051 g; 0.607 mmole) was added and the mixture was stirred for a little while. 4-(Trifluoromethylthio)phenyl isocyanate (0.126 g; 0.575 mmole) was added. The reaction mixture was stirred at room temperature for 6 hours and then evaporated to dryness. Ethyl acetate and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography of residue on silica gel (isolute, SI) using dichloromethane, methanol:dichloromethane (1:99) and then methanol:dichloromethane (2:98) as eluants gave 0.17 g (57% yield) of (S)-2-ethoxy-3-[4-(2-{4-[({4-[(trifluoromethyl)sulfanyl]anilino}carbonyl)amino]phenyl}ethoxy)phenyl]propanoic acid.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:26]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CN(C)CCN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc2c(c1)C(=NCCN(C)C)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
In this example, 22.0 g of methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate and 68.7 g of N,N-dimethylethylenediamine are dissolved in 700 ml of dried benzene. To the solution is dropwise added a solution of 17.2 ml of titanium tetrachloride in 40 ml of dried benzene and the mixture is stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution is added thereto. After removing an insoluble solid by filtration, the filtrate is extracted with 500 ml of ethylacetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order, and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the residue is purified by column chromatography on silica gel with ethylacetate/triethylamine (10/1) as an eluent to obtain 13.8 g of the desired product as a colorless oily matter.