Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][C@@H:16]([C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:71]2[CH:76]=[CH:75][C:74]([NH:77][C:78](=[O:101])[C@H:79]([CH2:93][C:94]([O:96]C(C)(C)C)=[O:95])[NH:80][C:81](=[O:92])[CH2:82][C:83]3[C:91]4[C:86](=[CH:87][CH:88]=[CH:89][CH:90]=4)[NH:85][CH:84]=3)=[CH:73][CH:72]=2)[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:70])[C@H:48]([CH2:62][C:63]([O:65]C(C)(C)C)=[O:64])[NH:49][C:50](=[O:61])[CH2:51][C:52]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:54][CH:53]=3)=[CH:42][CH:41]=2)=[CH:35][CH:34]=1)=[O:31])[NH:17][C:18](=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:14])(C)(C)C>CO>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][C:18]([NH:17][C@H:16]([C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([CH:39]([C:71]3[CH:72]=[CH:73][C:74]([NH:77][C:78](=[O:101])[C@H:79]([CH2:93][C:94](=[O:95])[OH:96])[NH:80][C:81](=[O:92])[CH2:82][C:83]4[C:91]5[C:86](=[CH:87][CH:88]=[CH:89][CH:90]=5)[NH:85][CH:84]=4)=[CH:75][CH:76]=3)[C:40]3[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:70])[C@H:48]([CH2:62][C:63](=[O:64])[OH:65])[NH:49][C:50](=[O:61])[CH2:51][C:52]4[C:60]5[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=5)[NH:54][CH:53]=4)=[CH:42][CH:41]=3)=[CH:37][CH:38]=2)=[O:31])[CH2:15][C:13](=[O:12])[OH:14])=[O:29])=[CH:21]1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)Cc1c[nH]c2ccccc12)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)Cc3c[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)Cc3c[nH]c4ccccc34)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)C[C@H](NC(=O)Cc1c[nH]c2ccccc12)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CC(=O)O)NC(=O)Cc3c[nH]c4ccccc34)cc2)c2ccc(NC(=O)[C@H](CC(=O)O)NC(=O)Cc3c[nH]c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
A methanol solution containing trifluoroacetic acid (40%, 6 ml) was added to the tris[4-[β-t-butoxycarbonyl-N-[2-(1H-indol-3-yl)acetyl]-L-alanyl]aminophenyl]methane (50 mg) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and a portion of the residue was purified by preparative high performance liquid chromatography using methanol/trifluoroacetic acid (100/0.1) and water/trifluoroacetic acid (100/0.1) as a mixed eluent, to obtain 1.3 mg of the title compound.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])(CC)C.C1CCCCC1>C1COCC1>[C:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
Tert-butyl (2R)-2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate (Intermediate XXXVIII, 8.1 g, 22.8 mmol) was dissolved in dry THF (200 mL) and cooled to −78° C. Then added sec-butyllithium 1.4M in cyclohexane (32.6 mL, 45.6 mmol) over 30 minutes and continued mixing an additional 30 minutes before quenching with 20% ammonium chloride solution (200 mL). The mixture was warmed to rt and diluted with ethyl ether (200 mL). The organic phase was separated, washed with brine, dried in vacuo and purified on a silica gel column using a 100% to 99:1 gradient of methylene chloride to methanol as mobile phase to yield pure tert-buty (2R)-2-ethynylpyrrolidine-1-carboxylate. LC-MS m/z (minus t-butyl+1)=220. 1H NMR (CD3OD, 400 Mhz) 4.44 ppm (s, 1H), 3.44-3.37 (m, 1H), 3.34-3.25 (m, 1H), 2.61 (s, 1H), 2.08-1.85 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:20][CH:21]=1)(=[O:24])[CH3:23]
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1

Procedure:
A solution of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]piperidine (see Preparation 4) (0.57 g), acetic anhydride (1 ml) and acetic acid (1 ml) was heated on a steam bath for 3 hours and then evaporated. The residue was dissolved in water (2 ml) and the solution was made basic with sodium bicarbonate solution. The solid was filtered off, washed with water, dried and then chromatographed on silica gel eluting with dichloromethane/methanol (20:1). Earlier fractions contained impurity and pure product was eluted in the later fractions. The product fractions were combined and evaporated. The solid was crystallised from methanol to give the title compound, (0.34 g), m.p. 226°-228°.
Reaction SMILES: Cl.[CH2:2]([S:6]([NH:9][C@@H:10]([CH2:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7])CCC.CS([Cl:21])(=O)=O>>[ClH:21].[CH3:2][S:6]([NH:9][C@@H:10]([CH2:15][NH2:16])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCS(=O)(=O)N[C@@H](CN)C(=O)OC
Agent: Cl
Product: COC(=O)[C@H](CN)NS(C)(=O)=O

Procedure:
5-7 was prepared as described above for the butylsulfonylamino analog (5-6) using methanesulfonyl chloride at the appropriate stage.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[N:21]1([C:26]2[CH:45]=[CH:44][C:29]([CH2:30][C:31]3[C:32]([Cl:43])=[N:33][C:34]4[C:39]([C:40]=3[Cl:41])=[CH:38][C:37](Br)=[CH:36][CH:35]=4)=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][C:31]3[C:32]([Cl:43])=[N:33][C:34]4[C:39]([C:40]=3[Cl:41])=[CH:38][C:37]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[OH:9])=[CH:36][CH:35]=4)=[CH:44][CH:45]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: O=C(c1cccnc1)c1cccc(F)c1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Product: OC(c1cccnc1)(c1cccc(F)c1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1

Procedure:
The title compound was prepared analogously to the method in Intermediate 37 using (3-fluorophenyl)(pyridin-3-yl)methanone (Intermediate 34: step b) in place of (4-chlorophenyl)(pyridin-3-yl)methanone, except that 1.2 equivalents of Intermediate 34: step b and 1.1 equivalents of n-BuLi were used relative to 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 3: step c).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:37]1[CH2:38][CH2:39][N:34]([C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:35][CH2:36]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCCC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 9 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-(piperazin-1-yl)pentan-1-one as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[NH:3]1.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]4[NH:3][C:2](=[O:1])[NH:16][C:5]4=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1
Solvent: CC#N
Product: O=C(c1cc2cc3[nH]c(=O)[nH]c3cc2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,2,3,5-tetrahydro-imidazo[4,5-f]indole-6-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: >270° C. (acetonitrile).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][C@@H:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=2)=[O:21])[CH2:13][CH2:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34]OS(C)(=O)=O>>[N:1]1([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][C@@H:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:34][C@@H:30]4[CH2:31][CH2:32][CH2:33][O:29]4)=[CH:24][N:23]=2)=[O:21])[CH2:13][CH2:12]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Reactant: O=C(N[C@H]1CCc2cc(CN3CCCCCC3)ccc2C1)c1ccc(O)cn1
Product: O=C(N[C@H]1CCc2cc(CN3CCCCCC3)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cn1

Procedure:
According to method F, 5-hydroxypyridine-2-carboxylic acid ((S)-6-azepan-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-2-yl)amide was alkylated with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester (DMF, 12 h, 80° C.). The product was thus obtained with the molecular weight of 463.63 (C28H37N3O3); MS (ESI): 464 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][NH2:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][NH:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)(=[O:19])=[O:20])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NNC(=O)c2ccccc2Cl)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 2-chlorobenzoyl chloride (22.3 g, 127.43 mmol) in toluene (200 mL). To the mixture was added 4-methylbenzenesulfonohydrazide (23.3 g, 125.27 mmol). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 75° C. in a bath of oil. A filtration was performed. The filter cake was dried in an oven under reduced pressure. This resulted in 37.7 g (91%) of 2-chloro-N′-tosylbenzohydrazide as a white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([OH:37])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:56]1[C:61]([F:62])=[C:60]([F:63])[C:59]([F:64])=[C:58]([F:65])[C:57]=1[F:66])=O>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](=[O:37])[O:36][C:56]3[C:57]([F:66])=[C:58]([F:65])[C:59]([F:64])=[C:60]([F:63])[C:61]=3[F:62])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.25 h

Procedure:
To a second flask containing #32 (360 mg, 0.59 mmol) in dichloromethane (0.6 mL, 1 M) and pyridine (0.095 mL, 1.2 mmol, 2 eq.) was added drop-wise pentafluorophenyl trifluoroacetate (0.203 mL, 1.18 mmol). This reaction mixture was stirred for 15 minutes.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:34][CH:35]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(Cc2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 1-(4-bromo-benzyl)-4-methyl-piperazine (56.0 mg, 0.208 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a pale yellow foam (0.010 g, 12%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.4 Hz, 1H), 8.24 (d, J=8.2 Hz, 2H), 8.09 (d, J=8.2 Hz, 2H), 7.66 (d, J=7.1 Hz, 1H), 7.54 (d. J=7.8 Hz, 2H), 7.31 (d, J=7.9 Hz, 2H), 7.02 (t, J=6.7 Hz, 1H), 6.86 (s, 1H), 3.49 (s, 2H), 3.11 (s, 3H), 2.46 (br s, 8H), 2.29 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH3:42])=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a white foam (320 mg, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccc(OC(C)C)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]=[C:23]([CH3:25])[CH3:24].B(F)(F)F.CCOCC>C(#N)C>[CH3:22][C:23]1([CH3:25])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=2)[NH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:24]1
Reactant: C=C(C)C
Reactant: O=[N+]([O-])c1cccc(/C=N/c2ccc(C(F)(F)F)cc2)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
A mixture of [1-(3-nitro-phenyl)-meth-(E)-ylidene]-(4-trifluoromethyl-phenyl)-amine (18.2 g of crude, 62.1 mmol), isobutene (52 mL, 620.6 mmol) and boron trifluoride etherate (1.6 mL, 12.4 mmol) in acetonitrile in a hydrogenated kettle was stirred for two days at room temperature. The solution was evaporated in vacuo and the residue was crystallized by treating with ethyl acetate to give 5.9 g of 4,4-Dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (yield: 27.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.C1([C:21](=[O:30])[CH2:22][C:23]2[CH:24]=[C:25](C)[CH:26]=[CH:27][CH:28]=2)C=CC=CC=1>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:21](=[O:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Cc1cccc(CC(=O)c2ccccc2)c1
Reactant: Clc1cc(Cl)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
To a solution of 1-bromo-3,5-dichlorobenzene (1 g, 4.4 mmol) in anhydrous THF (10 mL) was added n-BuLi (339 mg, 5.3 mmol) at −78° C. After being stirred for 30 minutes, a solution of N-methoxy-N-methyl-2-phenyl-acetamide (prepared following step 1 of Intermediate 4) (790 mg, 4.4 mmol) in THF (5 mL) was added, and the mixture was stirred for 3 hours. When TLC indicated that starting material was consumed, the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (20 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuum, and purified by column chromatography (PE:EtOAc=50:1) to afford 1-(3,5-dichlorophenyl)-2-phenylethanone (213 mg, yield 19.4%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:28](O)=[O:29])[CH:6]=1)[CH2:2][CH2:3][CH3:4].P(C#N)(=O)(OCC)OCC.[Cl:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.Cl>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:28]([NH:46][C:45]2[CH:47]=[CH:48][C:42]([Cl:41])=[CH:43][CH:44]=2)=[O:29])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1cc(C(=O)Nc2ccc(Cl)cc2)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A solution of 5-butyl-1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]pyrazole-3-carboxylic acid (0.8 g) and diethyl phosphorocyanidate (90% purity, 0.76 g) in DMF (6 ml) was allowed to stir at 0°-5° C. for 1 hour. 4-Chloroaniline (0.25 g) and triethylamine (0.62 g) were added to the solution and the mixture was stirred at room temperature for 3 hours. The reaction solution was made acidic by addition of 1N-HCl and extracted with ethyl acetate. The organic layer was dried and evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give colorless powder (0.38 g, 38%),
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C[O:18][C:19]([CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:20].CS(C)=O>O.Cl>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][N:27]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:22]([CH2:21][C:19]([OH:20])=[O:18])[CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
Solid K2CO3 (1070 mg, 7.74 mmol) was added to a mixture of 1-fluoro-2-nitrobenzene (655 mg, 4.65 mmol) and the product of Example 22B (1000 mg, 3.87 mmol). Dimethyl sulfoxide (40 mL) was added, and the mixture was heated at 100° C. with stirring under nitrogen. After 22 hours, additional 1-fluoro-2-nitrobenzene (350 mg) was added and heating was continued for 14 hours longer. The mixture was cooled to 40° C., diluted with water (400 mL), and aqueous 10% HCl (25 mL) was added to bring the pH˜3-4. The mixture was extracted with CHCl3 (4×200 mL). The combined extract was concentrated under vacuum to a residue that was purified by chromatography (SiO2, eluted with hexanes-ethyl acetate, 100:0-50:50-0:100) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.34-2.55 (m, 1H), 2.73-2.90 (m, 1H), 3.20-3.42 (m, 2H), 3.55-3.82 (m, 4H), 3.93-4.12 (m, 1H), 7.13-7.23 (m, 2H), 7.45-7.55 (m, 1H), 7.74 (dd, J=7.9, 1.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[N:9]=1)[CH2:2][C:3]#[CH:4].[I-].[K+].[C:19](/[C:21](=[N:28]\[O-:29])/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:20].[Na+]>C(#N)C.CN(C=O)C>[CH2:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:29]/[N:28]=[C:21](\[C:19]#[N:20])/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]=1)[CH2:2][C:3]#[CH:4]
Reactant: N#C/C(=N\[O-])c1ccccc1
Reactant: C#CCCOC(=O)Nc1cccc(CCl)n1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C#CCCOC(=O)Nc1cccc(CO/N=C(\C#N)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Phenylacetonitrile (9.72 g, 82.97 mmol) was metered into a suspension of 3.31 g (82.97 mmol) of NaOH in 60 ml of ethanol. Following the complete addition, 11.66 g (99.56 mmol) of isopentyl nitrite were metered in dropwise at temperatures of 15° C. The mixture was then stirred for a further 2 hours at this temperature. The reaction mixture was diluted with 300 ml of diethyl ether, and the precipitated solid was filtered off and washed twice with in each case 50 ml of diethyl ether. The white salt sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide (7.89 g, 56% yield) can be dried in vacuo or be further used directly. 1.49 g (6.24 mmol) of but-3-yn-1-yl[6-(chloromethyl)pyridin-2-yl]carbamate and 103 mg (0.624 mmol) of potassium iodide were added to a solution of 1.05 g (6.24 mmol) of sodium {[(Z)-cyano(phenyl)methylene]amino}oxidanide in 25 ml of acetonitrile and 10 ml of DMF. The reaction mixture was stirred for 7 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in 100 ml of ethyl acetate. The organic phase was washed with water and dried over MgSO4. After removing the solvent, 2.21 g (99% yield, only 1 oxime isomer) of but-3-yn-1-yl{6-[({[(Z)-cyano(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate were isolated as a colourless solid.