Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1coc(-c2cccc(F)c2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1coc(-c2cccc(F)c2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 9 %

Procedure:
This compound was synthesized from 2-(2-(3-fluorophenyl)oxazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (15 mg, yield 9%). 1H NMR (400 MHz, MeOD) δ 9.39 (d, J=2.0 Hz, 1H), 9.19 (d, J=2.3 Hz, 1H), 8.90-8.88 (t, J=2.1 Hz, 1H), 7.84-7.82 (m, 2H), 7.72-7.69 (m, 1H), 7.54-7.49 (m, 1H), 7.26-7.21 (m, 1H), 3.79-3.76 (t, J=6.9 Hz, 2H), 2.98-2.95 (t, J=6.9 Hz, 2H). MS (ESI) m/z: Calculated for C20H13F4N5O3: 447.10. found: 448.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:28]2[CH:37]=[C:36]([C:38](O)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:41])[CH:34]=3)[N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:28]2[CH:37]=[C:36]([C:38]([NH:1][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]5[CH2:20][CH2:19]5)=[O:15])=[CH:10][CH:9]=4)[C:5]([CH3:21])=[CH:4][CH:3]=3)=[O:39])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:41])[CH:34]=3)[N:29]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: Cc1ccc2nc(C3CCCCC3)cc(C(=O)O)c2c1
Solvent: C1CCOC1
Product: Cc1ccc2nc(C3CCCCC3)cc(C(=O)Nc3ccc(C)c(-c4ccc(C(=O)NCC5CC5)cc4)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (42 mg, 0.15 mmol) and 2-cyclohexyl-6-methylquinoline-4-carboxylic acid (107.7 mg, 0.4 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 30 min at room temperature. Carbodiimde resin (442 mg, 0.5 mmol) was added and shaking continued for 18 h. The solution was filtered off, the resin washed with THF and methanol and the combined filtrate and washings reduced to dryness under vacuum. The residue was dissolved in ethyl acetate, washed with hydrochloric acid (1M) and aqueous sodium hydrogen carbonate. The solvent was evaporated from the organic fraction under vacuum to give 2-cyclohexyl-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-6-methylquinoline-4-carboxamide. NMR; δH [2H6]—DMSO 10.69,(1H, s), 8.62,(1H, t), 7.95-7.90,(3H, m), 7.82,(1H, s), 7.70,(2H, m), 7.60,(1H, dd, 7.56, (1H, s), 7.46,(2H, d), 7.33,(1H, d), 3.16,(2H, t), 2.90,(1H, m), 2.47,(3H, s), 2.22,(3H, s), 1.95,(2H, m), 1.84,(2H, m), 1.74-1.61,(3H, m), .46-1.26,(3H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.93 min, MH+532.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([C:11]([O:13]C)=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:15]>CO>[N:1]1[C:10]2[CH:9]([C:11]([NH2:15])=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: COC(=O)C1CCCc2cccnc21
Solvent: CO
Product: NC(=O)C1CCCc2cccnc21
Temperature: 100 °C

Procedure:
Methyl 5,6,7,8-tetrahydroquinoline-8-carboxylate (9 g.) was dissolved in methanol previously saturated with ammonia (270 ml.) and heated in a bomb at 100° C. for 5 days. The solvent was removed and the residual oil triturated with hot petroleum ether (40°-60°). The resultant solid was filtered and then recrystallised from ethyl acetate giving the title compound as colourless needles mpt. 132° C. (5 g.). Found: C, 67.7; H, 7.1; N, 16.0% C10H12N2O requires: C, 68.1; H, 6.9; N, 15.9%.
Reaction SMILES: [CH2:1](Cl)CCl.[CH3:5][CH2:6][C:7]1[C:12]2[NH:13][C:14]([CH2:17][NH2:18])=[C:15]([CH3:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.[O:20]=[C:21]1[CH2:26][O:25][C:24]2[CH:27]=[C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)[CH:29]=[N:30][C:23]=2[NH:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:6]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:12]=1[NH:13][C:14]([CH2:17][N:18]([CH3:1])[C:33](=[O:35])/[CH:32]=[CH:31]/[C:28]1[CH:29]=[N:30][C:23]3[NH:22][C:21](=[O:20])[CH2:26][O:25][C:24]=3[CH:27]=1)=[C:15]2[CH3:16])[CH3:5]
Reactant: ClCCCl
Reactant: CCc1cccc2c(C)c(CN)[nH]c12
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(C)c(CN(C)C(=O)/C=C/c3cnc4c(c3)OCC(=O)N4)[nH]c12
Reaction time: 8 h
Yield: 12.4 %

Procedure:
EDC (147 mg, 0.7 mmol) was added to a solution of (7-ethyl-3-methyl-1H-indol-2-yl)-N-methanamine (108.7 mg, 0.5 mmol), (E)-3-(3-oxo-3,4,dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid hydrochloride (151 mg, 0.6 mmol), HOBT.H2O (73 mg, 0.5 mmol) and DIPEA (0.39 mL, 2.1 mmol) in dry DMF (5 mL). After stirring overnight, water was added. The precipitate that formed was washed with ethyl acetate and dried to afford the title compound (25 mg, 0.001%). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.92 (s, 1H), 8.15 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.05 (m, 2H), 6.80 (d, J=7.5 Hz, 1H), 4.70 (s, 2H), 3.15 (s, 3H), 2.88 (q, J=7.0 Hz, 2H), 2.40 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI): m/e 405.2 (C23H24N4O3+H)+.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[C:37]([C:41]1[CH:77]=[CH:76][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[C:50]([C:72]([F:75])([F:74])[F:73])[CH:49]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:77]=[CH:76][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([OH:67])=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[C:50]([C:72]([F:74])([F:75])[F:73])[CH:49]=2)=[O:46])=[CH:43][CH:42]=1)([CH3:39])([CH3:40])[CH3:38]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3C(F)(F)F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3C(F)(F)F)cc2C1=O
Yield: 71 %

Procedure:
The compound of example 424 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 423.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=[C:13]([F:16])[CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:32](=[O:34])=[O:33]>C1COCC1>[C:20]([O:19][C:18]([NH:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][N:7]2[CH:6]([C:5]1[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:32]([OH:34])=[O:33])=[O:24])([CH3:22])([CH3:23])[CH3:21]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)cc2c1ccn2Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)cc2c1ccn2C(C(=O)O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To the mixture of tert-butyl 1-(4-chlorobenzyl)-6-fluoro-1H-indol-4-ylcarbamate (8 g, 0.021 mol) in THF (300 mL) was added dropwise BuLi (2.5 M, 34 mL, 0.084 mol) at −78° C. and the mixture was stirred for another 30 min at −78° C. An excess of dry ice was added and the solution was warmed slowly to room temperature. The resulting mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with EA and washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound (8 g, yield 89%). LC/MS m/z=363.1 [M-tBu+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[CH3:13][O:14][C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:27]([N:29]2[CH2:34][CH2:33][C:32]3([CH2:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:45]#[N:46])[CH:40]=4)[O:35]3)[CH2:31][CH2:30]2)=[O:28])[CH:16]=1.[OH-].[Na+]>O.CN(C=O)C>[CH3:13][O:14][C:15]1[C:24]2[C:19](=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:27]([N:29]2[CH2:34][CH2:33][C:32]3([CH2:43][C:42](=[O:44])[C:41]4[C:36](=[CH:37][CH:38]=[C:39]([C:45]5[NH:46][N:3]=[N:2][N:1]=5)[CH:40]=4)[O:35]3)[CH2:31][CH2:30]2)=[O:28])[CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C#N)ccc2O3)nc2c(OC)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Temperature: 100 °C
Reaction time: 20 h

Procedure:
Alternatively, 195 mg of sodium azide, 413 mg of triethylamine hydrochloride and 5 mL of DMF were added to the nitrile derivative (458 mg) produced in Example 16, and stirred at 100° C. under a nitrogen atmosphere for 20 hours. After cooled, the mixture was added by 30 mL of water and 0.60 mL of aqueous 5 N sodium hydroxide solution, then the mixture was washed five times with chloroform (10 mL each). 0.60 mL of 5 N hydrochloric acid was added to the aqueous layer, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated. The resulting residue was purified through silica gel chromatography (chloroform/methanol=50/1 to 30/1, chloroform/methanol/acetic acid=300/100/1), the fraction containing it was concentrated, and ethyl ether was added to the residue. The resulting insoluble material was taken out through filtration, washed with ethyl ether, and dried under reduced pressure to obtain the intended compound as a pale yellow powder. 1H-NMR (300 MHz, DMSO-d6) δ: 8.44 (1H, d, J=2.3 Hz), 8.26 (1H, dd, J=8.6, 2.3 Hz), 7.69 (1H, dd, J=8.4, 1.1 Hz), 7.53 (1H, dd, J=8.4, 7.8 Hz), 7.38 (1H, d, J=8.6 Hz), 7.25 (1H, dd, J=7.8, 1.1 Hz), 7.21 (1H, s), 4.38-4.30 (1H, m), 4.08 (3H, s), 3.95 (3H, s), 3.70-3.62 (1H, m), 3.52-3.43 (1H, m), 3.38-3.28 (1H, m), 3.02 (2H, s), 2.15-2.08 (1H, m), 1.99-1.82 (3H, m). MS [M+H]+=501
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][C:3]=1[O:14][CH3:15].C1(C)C=CC(S(Cl)(=O)=[O:23])=CC=1>>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([CH2:6][C:7]#[N:12])=[C:9]([CH:10]=1)[C:8]([OH:11])=[O:23]
Reactant: COc1cc2c(cc1Br)C(=O)C(=NO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1cc(CC#N)c(C(=O)O)cc1Br

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-5-methoxy-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 5-Bromo-2-cyanomethyl-4-methoxy-benzoic acid. LC-MS: m/e 268 (M−1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=O)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[N+:1]([C:4]1[C:5]([CH2:14][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1c(CNc2ccccc2)ccc2cccnc12
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of 8-nitro-quinoline-7-carbaldehyde (Intermediate 204) (500 mg, 2.4 mmol) and aniline (270 μl, 2.9 mmol) in MeOH (20 ml) under a nitrogen atmosphere was stirred at room temperature for 16 hours. Sodium borohydride (269 mg, 7.1 mmol) was added and stirring continued at room temperature for 1 h. The reaction mixture was concentrated in vacuo and residue was diluted with sat. NaHCO3 solution (30 ml) and was extracted with DCM. The organic phases were dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc gradient elution to give the title compound (0.48 g, 69%).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:6]1([CH2:22][CH2:23][CH3:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:4][CH3:5]>O.C(O)C>[CH2:22]([C:6]1([CH2:3][CH2:4][CH3:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:23][CH3:24]
Reactant: CCCC1(CCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1ccc2c(c1)C(CCC)(CCC)CCS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.82 g (32.4 mmol) of potassium hydroxide in 1.8 mL of water and 10.0 mL of ethanol was added to 1.22 g (3.70 mmol) of (4,4-dipropylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 30) and the resulting mixture stirred at room temperature for 5 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aq H2SO4 and the product was extracted with 2×50 mL of ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:24](O)=[O:25])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:40][C:41]1[CH:46]=[CH:45][N:44]=[C:43](Cl)[CH:42]=1>O1CCCC1>[N:44]1[CH:45]=[CH:46][C:41]([NH:40][C:24](=[O:25])[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccccc2)c1)C(=O)O
Reactant: Nc1ccnc(Cl)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ccncc1
Reaction time: 0.25 h
Yield: 11.6 %

Procedure:
N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine (4.40 g) was dissolved in dry tetrahydrofuran (100 ml) and triethylamine (1.80 ml) was added under ice-cooling, followed by stirring for 15 minutes. To this solution was added ethyl chlorocarbonate (1.44 g) and the mixture was stirred for 30 minutes. After adding 4-amino-2-chloropyridine (1.54 g), the reaction was carried out at room temperature for 10 hours. Thereafter, the solid was filtered off and the filtrate was concentrated under a reduced pressure. The residue was extracted with ethyl acetate. The extract was purified with a column chromatography (hexane/ethyl acetate=3/1) to obtain N-(t-butoxycarbonyl)-3-phenoxy-DL-phenylalanine 4-(2-chloro)pyridylamide (I) (0.60 g), which was confirmed by the following NMR analysis, in the form of a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([N-:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])#[N:17]>>[C:24]1([CH2:23][CH2:22][NH:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=2)/[C:16]#[N:17])=[O:20])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Reactant: N#CCC(=O)[N-]CCc1ccccc1
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCCc2ccccc2)cc(OC)c1O
Yield: 82.6 %

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.1 g, 0.48 mmol) to N-(cyanoacetyl)phenylethylamide (Example 20, 0.091 g, 0.48 mmol). The residue was purified by silica gel chromatography (CHCl3-hexane, 1:1) to give a yellow solid (0.15 g, 83% yield). The product gave the following analytical data:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1[N:44](P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:54]([N:56]([CH2:59]C)[CH2:57]C)[CH3:55].CNCCNC>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:26])[F:28])=[N:20][C:21]([C:22](=[O:24])[NH:44][CH2:55][CH2:54][N:56]([CH3:59])[CH3:57])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: CNCCNC
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 59.7 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.14 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of dichloromethane under stirring, and N,N′-dimethylethane-1,2-diamine (48 mg, 0.54 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(2-dimethylamino-ethylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 29a (0.1 g) as a white solid.
Reaction SMILES: [Cl:1]C1C=CC=C2C=1NC=C2C=O.[C:13]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](Cl)[CH:23]=2)[N:18]([CH2:26][C:27]([OH:29])=[O:28])[CH:17]=1)(=[O:15])[NH2:14]>>[C:13]([C:16]1[C:24]2[C:19](=[C:20]([Cl:1])[CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:26][C:27]([OH:29])=[O:28])[CH:17]=1)(=[O:15])[NH2:14]
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Reactant: O=Cc1c[nH]c2c(Cl)cccc12
Product: NC(=O)c1cn(CC(=O)O)c2c(Cl)cccc12

Procedure:
was prepared from 7-chloro-1H-indole-3-carbaldehyde [1008-07-7] using similar protocols as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 253 [M+H]+, 505 [2M+H]+; tR (HPLC conditions b): 3.32 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]=[O:34])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.CCCCCC>[CH2:13]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]([C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1)[OH:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1cc(Br)cn1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cn1cc(C(O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2Cc2ccccc2)cn1
Reaction time: 0.75 h
Yield: 64.6 %

Procedure:
To a solution of 4-bromo-1-methylpyrazole (170.7 g) in diethyl ether (2 l) was added dropwise n-butyllithium (1.6N) in hexane (713 ml) keeping the temperature below -60° C. After stirring for 45 minutes, a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (260 g) in diethyl ether (200 ml) was added dropwise. After stirring for 30 minutes, the mixture was warmed to 0°~5° C. over 2.5 hours and stirred for 45 minutes. The reaction mixture was quenched with ice water (1 l) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (×2), and the combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (3.5 kg, eluting with n-hexane:AcOEt=3:2 to 1:1 to 0:1) to give (2S,4R)-1-{1-benzyl-4-(t-butyldimethyl-silyloxy) pyrrolidin-2-yl}-1-(1-methyl-4-pyrazolyl)methanol (211.2 g) as a 1:1 mixture of diastereomers.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:36])[CH3:35]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A166) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:14]3)[NH:12][C:11](=[O:28])[C:10]=2[CH:29]=1.[OH-].[Na+]>O.O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[CH2:16][CH2:17][CH2:18][C:13]3([NH:12][C:11](=[O:28])[C:10]4[CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=[CH:8][C:9]=4[O:27]3)[CH2:14]2)=[CH:21][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccc(F)cc3)C1)O2

Procedure:
A solution of (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (300 mg, 0.73 mmol) in water (2.5 ml) and dioxane (5 ml) was treated with 1 M NaOH (0.95 ml) as described in Example 30, Step A to give (±)-(E)-3-{1′-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid as a white solid [LC-MS: (ES+) MH+: 397]. The obtained acrylic acid was suspended in DCM (5 ml), treated with TEA (0.15 ml, 1.1 mmol) and then with EDC (208 mg, 1.09 mmol), HOBt (147 mg, 1.09 mmol) and NH2OTHP (102 mg, 0.87 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{t-(4-fluoro-benzyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (60 mg) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[C@@H:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C@H:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1
Reactant: Oc1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure B and Scheme B1 using 3-chlorophenol and N-(3-{1-[(2S)-2-hydroxy-2-phenylethyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 478.5 (M+H)+.