Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]1.[NH2:15][OH:16]>C(O)C>[OH:16][NH:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C@H:5]2[CH2:6][C@H:4]2[CH2:3][CH2:2][OH:1])[CH2:8][CH2:9]1)=[NH:14]
Reactant: N#CN1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: NO
Solvent: CCO
Product: N=C(NO)N1CCC([C@H]2C[C@H]2CCO)CC1
Temperature: 65 °C

Procedure:
4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carbonitrile (4.1 g, 21.10 mmol) was dissolved in Ethanol (60 ml) and hydroxylamine (5.17 ml, 84 mmol) (50% water solution) was added dropwise. The mixture was heated at 65° C. for 1 h. The mixture was evaporated to afford the desired product which was used for the next step without further purification. Rf was 0 @ 70% EtOAc in hexanes (blue spot on CAM stain)
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>ClCCl>[CH2:1]([C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][CH2:17][CH:18]([O:23][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:19]([CH3:21])([CH3:20])[CH3:22])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol (7.5 g, 20 mmol) in dichloromethane (100 ml) at −78° C. is added 2,6-dimethylpyridine (5.8 ml, 50 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (6.0 ml, 26 mmol). After stirring at RT for 2 h, the reaction diluted with dichoromethane and washed successively with 1N HCl followed by satd NaHCO3. The organic layer is dried over MgSO4 and concentrated to give the title product (9.5 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[C:24](Cl)(Cl)=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][C:24]([OH:25])=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnc(O)o2)cc2[nH]cnc2c1F
Temperature: 25 °C
Yield: 99 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.050 g, 0.150 mmol) is suspended in PhMe (2 mL) and a 20% phosgene solution in PhMe (0.24 mL, 0.45 mmol) is added. The reaction mixture is stirred at reflux under N2 for 1 hour and then cooled to room temperature. The reaction mixture is quenched by the addition of a 1:1 mixture of THF and 10% HCl (20 mL). The layers are separated and the aqueous layer is extracted with THF (3×). The combined organic layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give 54 mg (99%) of desired product as a yellow solid: LC/MS ESI (+) m/z 360, 362 (M+Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.83 (s, 1H), 7.88 (s, 1H), 7.30 (s, 1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.38 (dd, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[N:11]=[C:21]([C:20]4[CH:24]=[CH:25][C:17]([C:14](=[O:16])[CH3:15])=[CH:18][CH:19]=4)[O:13][N:12]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: N=C(NO)C1CCN(C2CC2)CC1
Reactant: CC(=O)c1ccc(C(=O)Cl)cc1
Product: CC(=O)c1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidine and 4-acetylbenzoyl chloride.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O:23]C)=[O:22])[C:15]2[N:19]=[CH:18][NH:17][C:16]=2[CH:20]=1)=[O:10].[OH-].[Na+]>CO>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([OH:23])=[O:22])[C:15]2[N:19]=[CH:18][NH:17][C:16]=2[CH:20]=1)=[O:10]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]cnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1cc(C(=O)O)c2nc[nH]c2c1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Methyl 6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylate (356 mg) was dissolved in MeOH (10 mL), and 1N aqueous sodium hydroxide solution (2 mL) was added, and the reaction mixture was stirred at room temperature overnight. After MeOH was removed under reduced pressure, water was added to the residue, and the solution was acidified with 1N hydrochloric acid to pH 5 under ice-cooling. The precipitate was collected by filtration to obtain the titled compound (276 mg) as slightly brown powder.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH3:30]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:20]([F:19])[CH:21]=2)=[O:33])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Reactant: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Solvent: CC#N
Product: COCCOc1ccc(NC(=O)NCc2cc(C(C)(C)C)nn2-c2cccc(Cl)c2)cc1F

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (synthesis described for example A18) (81 mg, 0.31 mmol, 1.0 eq.) in MeCN (7 mL) was added TEA (0.17 mL, 1.2 mmol, 4.0 eq.) followed by phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (95 mg, 0.31 mmol, 1.0 eq.) at RT and stirred at reflux for 16 h. The solvent was evaporated under vacuum. The crude product obtained was purified by column chromatography (eluent EtOAc/n-hexane 1:1) to yield example A17 (121 mg; 83%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2.Cl>CCCCCC.CCOCC>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN1C2CCC1CC(O)(c1ccc(F)cc1)C2
Temperature: -45 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of dry ether (600 ml) and 15% BuLi in hexane (500 ml) was cooled to -45° C. A solution of 4-bromo-1-fluorobenzene (145 g) in dry ether (350 ml) was added dropwise at -45° C. followed by stirring for 1 h. A solution of 8-methyl-8-azabicyclo[3,2,1]octan-3-one (85 g) in dry ether (400 ml) was added dropwise at -50° C. followed by stirring for 30 min, the temperature raising to -20° C. The reaction mixture was poured into 2 M hydrochloric acid and the phases separated. The ether phase was extracted with 2 M hydrochloric acid and the combined aqeous phases made alkaline with aqeous NaOH. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate and removal of solvent in vacuo, gave 3-(4-fluorophenyl)-3-hydroxy-8-methyl-8-azabicyclo[3,2,1]octane (96 g) as a solid, mp: 169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccncc1
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Clc1cccc(-c2nc(Nc3ccncc3)c3nccnc3n2)c1

Procedure:
The title product was synthesized by reaction of the 2-(3-chlorophenyl)pteridin-4-one with 4-aminopyridine following the procedure described for 4-[(butyl)(4-pyridyl)-amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2C(O)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(CNc2ccnc3ccc(C#N)cc23)cc1Cl
Temperature: 240 °C
Yield: 75.3 %

Procedure:
To 2.16 g (5.87 mmol) 4-[[(3-chloro-4 -methoxyphenyl)-methyl]amino]-6-cyano-3-quinolinecarboxylic acid was added 50 mL diphenyl ether (Aldrich), and nitrogen was vigorously bubbled through this mixture for 20 minutes. The resulting mixture was then heated to 240° C. under nitrogen for 30 minutes. During the course of the reaction, the dispersed starting material slowly dissolved, and gas evolution was observed. The resulting solution was poured into 200 mL hexane, and a precipitated solid was filtered to yield 1.43 g (4.42 mmol, 75% yield) of the title compound as a off-white solid: LC/MS: M/Z 324 (M+H) observed, 96% purity; mp: decomposed 227-230° C. LC: 2.84′.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:21])[CH2:11][C:12]#[C:13][Si](CC)(CC)CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:23]1[CH:29]=[C:28]([N:30]2[CH:34]=[N:33][N:32]=[CH:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25].[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N#N>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][CH2:9][C@H:10]([OH:21])[CH2:11][C:12]1[C:23]2[C:24](=[CH:26][CH:27]=[C:28]([N:30]3[CH:34]=[N:33][N:32]=[CH:31]3)[CH:29]=2)[NH:25][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](C#CC[C@@H](O)COCc1ccccc1)(CC)CC
Reactant: Nc1ccc(-n2cnnc2)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CN(C)C=O
Product: O[C@@H](COCc1ccccc1)Cc1c[nH]c2ccc(-n3cnnc3)cc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 26.5 %

Procedure:
This acetylene (7.6 g, 25 mmol), 2-iodo-4-(1,2,4-triazol-4-yl)aniline (5.6 g, 19.6 mmol), LiCl (927 mg, 19.7 mmol), Na2CO3 (8.37 g, 79 mmol), and Ph3P (1.03 g, 3.93 mmol) were stirred in DMF (200 ml) at r.t. for 2 h whilst N2 gas was bubbled through the mixture. Pd(OAc)2 (441 mg, 1.97 mmol) was then added, and the reaction heated at 100° C. for 20 h. The mixture was cooled, filtered and evaporated. H2O (500 ml) was added, and extracted with ethyl acetate (×5). The combined organic layers were washed with H2O, brine, dried, and evaporated. A mixture of EtOH and 5M HCl (300 ml, 1:1 v/v) was added, and the solution stood at r.t. for 18 h, then poured into saturated K2CO3, and extracted with EtOAc (×3). The organic layers were washed with water and brine, dried, evaporated, and purified by flash chromatography, eluting with CH2Cl2 :MeOH (92:8 v/v) to give (R)-3-(3-benzyloxy-2-hydroxyprop-1-yl)-5-(1,2,4-triazol-4-yl)indole (1.81 g, 26%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]2[CH2:11][NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[ClH:19].[CH3:20][N:21]([CH2:23][CH2:24][CH2:25][Cl:26])[CH3:22]>>[ClH:26].[ClH:19].[ClH:26].[NH2:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:5]2[CH:11]([CH2:25][CH2:24][CH2:23][N:21]([CH3:22])[CH3:20])[NH:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN(C)CCCCl
Reactant: Nc1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Agent: Cl
Product: CN(C)CCCC1NCCc2nc(N)nc(-c3ccc(F)cc3)c21
Yield: 25.3 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.0 g, 8.2 mmol) and dimethylaminopropylchloride hydrochloride (2.6 g, 16.4 mmol) to give 0.91 g (34%) of 2-amino-4-(4- fluorophenyl)-5,6,7,8-tetrahydro-5-(3-dimethylaminopropyl)pyrido[4,3-d]pyrimidine trihydrochloride. m.p. 241°-243° C. MS: 329(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][O:12]CC)=[N:6][C:5]=1[NH2:15].C(=O)(O)[O-].[Na+].[BH4-].[Na+].C(OCC)(=O)C>Cl.C(O)C.O1CCCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[N:6][C:5]=1[NH2:15]
Reactant: CCOC=Cc1ccc(C(=O)OC)c(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(CCO)nc1N
Reaction time: 3 h
Yield: 39.9 %

Procedure:
2-Amino-6-(2-ethoxy-vinyl)-nicotinic acid methyl ester (1.07 g, 4.81 mmol) was dissolved in 5N-hydrochloric acid (25 mL), ethanol (20 mL) and tetrahydrofuran (5 mL), and the solution was stirred for 3 hours under reflux. This reaction mixture was allowed to room temperature, and neutralized with a aqueous solution of saturated sodium bicarbonate, then, sodium borohydride (1 g, 26.5 mmol) was added to this reaction mixture, which was then stirred for 20 minutes at room temperature. Ethyl acetate was added thereto, followed by filtrating through Celite pad. This filtrate was partitioned. This organic layer was separated, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography, and the title compound (350 mg, 1.92 mmol, 40%) was obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([O:20][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=[C:11]2[CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCCCc2nc(C(C)C)n(Cc3ccc(Cl)c(Cl)c3)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 8 (300 mg) in anhydrous Tetrahydrofuran (THF) (3 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (102 mg, 2.55 mmol) as a 60% by weight suspension on mineral oil in one charge. The reaction was stirred at 0° C. for 30 min. To the reaction was added neat ethyl bromoacetate (0.284 mL) in one charge the reaction was then gradually allowed to warm to ambient temperature under an atmosphere of nitrogen over 20 hours. LCMS (high pH) showed a mixture of DP:SM (1:1). The reaction mixture was partitioned between EtOAc (50 ml) and sat NH4Cl aq sol (30 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (30 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was by column chromatography on silica using a Cyclohexane:Ethyl acetate 0-100% gradient+Ethyl acetate:Methanol 0-20% gradient. The desired fractions were combined and concentrated under vacuum to give the desired product, 220 mg, yellow oil. LC/MS MH+ 439/441, Rt 3.37 mins (5 min run, high pH).
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:18][C@H:17]([NH:19][C:20](=[O:32])[C@@H:21]([N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:24])[CH3:22])[C:16](=[O:33])[N:15]([CH2:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([Br:45])=[CH:42][CH:43]=4)[CH:38]=[CH:37][C:36]=3[O:46][CH3:47])[C:14]3[CH:48]=[CH:49][CH:50]=[CH:51][C:13]2=3)=[O:11])=[CH:6][CH:5]=1.O[Li].O>C1COCC1.CO.O.O>[Br:45][C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[C:35]([CH2:34][N:15]1[C:16](=[O:33])[C@@H:17]([NH:19][C:20](=[O:32])[C@@H:21]([N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH3:24])[CH3:22])[CH2:18][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:52])=[O:2])=[CH:5][CH:6]=3)=[O:11])[C:13]3[CH:51]=[CH:50][CH:49]=[CH:48][C:14]1=3)=[C:36]([O:46][CH3:47])[CH:37]=[CH:38]2
Reactant: COC(=O)c1ccc(C(=O)N2C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc3c(OC)ccc4cc(Br)ccc34)c3ccccc32)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2ccc(C(=O)O)cc2)c2ccccc21
Yield: 91.6 %

Procedure:
To a solution of 4-{(S)-5-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-3-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-carbonyl}-benzoic acid methyl ester (Intermediate 19) (4 g, 5.175 mmol) in THF-MeOH-water 1:1:1 (90 mL) were slowly added a solution of LiOH.H2O solution (574 mg, 13.6 m mol) in water. After 4 h the mixture was concentrated, the residue was diluted with water and acidified to pH˜3 with 1 N HCl. The mixture was extracted with ethyl acetate, the extracts were dried over sodium sulfate and evaporated. The residue was triturated with hexane to give the title compound (3.6 g, 91.58%) as an off white solid. LC-MS: 759 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])[O:11][C:10]2=O)=[CH:5][CH:4]=1.[CH2:21]([C:28]1[CH:32]=[CH:31][NH:30][C:29]=1CO)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:13]([CH:14]([CH3:16])[CH3:15])[C:12]([O:11][CH2:10][C:29]2[NH:30][CH:31]=[CH:32][C:28]=2[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:17])=[CH:5][CH:4]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1)C(=O)OCc1[nH]ccc1Cc1ccccc1

Procedure:
In the same way, 3-(4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with 3-benzylpyrrolylmethyl alcohol to give 3-benzylpyrrolylmethyl 2-(4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.O[CH2:13][CH:14]([CH2:16]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[N:6]=[CH:16][CH:14]=[CH:13]2
Reactant: OCC(O)CO
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc2cccnc12
Yield: 84.4 %

Procedure:
In a similar fashion using route 10 general procedure 20, 4-fluoro-2-nitroaniline (1.0 g, 6.41 mmol), glycerol (1.83 g, 19.9 mmol), 3-nitrobenzenesulfonic acid sodium salt (1.8 g, 8.33 mmol) and H2SO4/H2O (6 ml, 7:5) gave the title compound (1.04 g, 84%) which was used in the next step without purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[CH:29]=[CH2:30].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>C(Cl)(Cl)Cl>[C:31]([N:26]1[CH2:27][CH2:28][C@@H:23]([CH2:22][CH2:21][CH2:20][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[C@@H:24]([CH:29]=[CH2:30])[CH2:25]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C[C@H]1CNCC[C@H]1CCCc1ccnc2ccc(OC)cc12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C[C@H]1CN(C(=O)c2ccccc2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12

Procedure:
18.4 cm3 of triethylamine were added to a stirred solution of 20.8 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-3-vinylpiperidine in 270 cm3 of chloroform, followed, over 1 hour, by a solution of 7.2 cm3 of benzoyl chloride in 50 cm3 of chloroform. After stirring the mixture at a temperature in the region of 20° C. for 1 hour 30 minutes, 100 cm3 of distilled water were added to the reaction mixture. The chloroform phase was separated by settling, washed with 2 times 100 cm3 of water, and then dried over magnesium sulfate. After filtering through paper, the chloroform solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 25 g of (3R,4R)-1-benzoyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-3-vinylpiperidine were obtained in the form of a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([F:19])[CH:15]=[CH:14][CH:13]=3)[C:5]([CH:8]=[CH2:9])=[N:6][CH:7]=1.[ClH:20].O1CCOCC1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([F:19])[CH:15]=[CH:14][CH:13]=3)[C:5]([CH2:8][CH2:9][Cl:20])=[N:6][CH:7]=1
Reactant: C=Cc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1
Reactant: Cl
Solvent: C1COCCO1
Product: Fc1cccc2[nH]c(-c3cc(Br)cnc3CCCl)cc12
Yield: 90 %

Procedure:
A solution of 2-(5-bromo-2-vinylpyridin-3-yl)-4-fluoro-1H-indole (800 mg, 2.52 mmol) in 20 mL of HCl/1,4-dioxane (4 mol/L) was heated at 80° C. for 2 hours and then the mixture was concentrated in vacuo to give the crude 2-(5-bromo-2-(2-chloroethyl)pyridin-3-yl)-4-fluoro-1H-indole (800 mg, yield: 90%) which was used directly in the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 8.66 (s, 1H), 7.93 (s, 1H), 7.14˜7.22 (m, 2H), 6.73˜6.86 (m, 1H), 6.72 (s, 1H), 4.07˜4.10 (m, 2H), 3.35˜3.36 (m, 2H). MS (M+H)+: 353/355.