Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH2:24]OCC[Si](C)(C)C)[CH:20]=[C:21]([NH2:23])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]1([C@@H:46]([N:48]2[CH:52]=[C:51]([C:53](Cl)=[O:54])[CH:50]=[N:49]2)[CH3:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:32])[N:19]([CH3:24])[CH:20]=[C:21]([NH:23][C:53]([C:51]2[CH:50]=[N:49][N:48]([C@H:46]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH3:47])[CH:52]=2)=[O:54])[CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](c1ccccc1)n1cc(C(=O)Cl)cn1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(N)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccccc1)n1cc(C(=O)Nc2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(=O)n(C)c2)cn1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Intermediate (6c), 2-[5-Amino-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol) was stirred in dichloromethane (5 mL) at RT with triethylamine (0.092 mL, 0.66 mmol). The reaction mixture was cooled to 5° C. and then a solution of intermediate (6h), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, (54 mg, 0.231 mmol) in dichloromethane (1 mL) was added drop wise. After addition the reaction was stirred at RT for 1 hour and then the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (10 mL) and aqueous saturated sodium hydrogen carbonate solution (10 mL). The organic layer was separated and the aqueous was extracted with a further portion of ethyl acetate (10 mL). The combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—50% ethyl acetate/hexane (gradient) to afford the desired intermediate, 2-(1-Methyl-2-oxo-5-{[1-((S)-1-phenyl-ethyl)-1H-pyrazole-4-carbonyl]-amino}-1,2-dihydro-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester, 0.108 g, 76%.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33]1>>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([NH2:38])[CH2:33]1)=[O:24]
Reactant: Cc1cccc(C)c1-c1nc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: Cc1cccc(C)c1-c1nc(C(=O)Nc2cnccc2N2CCC[C@H](N)C2)c(N)s1
Yield: 13 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-(2,6-dimethylphenyl)thiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (8 mg, 13%). 1H NMR (400 MHz, DMSO) δ 9.22 (s, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.48 (s, 2H), 7.35-7.26 (m, 1H), 7.17 (d, J=7.7 Hz, 2H), 7.04 (d, J=5.3 Hz, 1H), 3.06 (t, J=14.4 Hz, 1H), 2.99 (d, J=11.7 Hz, 1H), 2.83-2.66 (m, 1H), 2.64-2.48 (m, 1H), 2.45-2.31 (m, 1H), 2.21 (s, 6H), 1.64 (dd, J=17.0, 6.8 Hz, 2H), 1.57-1.41 (m, 1H), 1.17-0.95 (m, 1H). ESIMS m/z=423.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[OH-].[Li+].Cl.ClCCl.CO>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][N:14]=[N:15][N:16]=2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Alternately, combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (1.71 g, 7.3 mmol) and an aqueous solution of lithium hydroxide (25 mL, 1 M) in methanol (40 mL). After 18 hours, heat to reflux. After 1 hour, add an aqueous solution of lithium hydroxide (15 mL, 1 M) and continue the reflux. After 15 hours, cool to ambient temperature, acidify with a 1 M aqueous hydrochloric acid solution and extract four times with ethyl acetate and then with dichloromethane. Combine the organic layers, dry over MgSO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with dichloromethane/methanol 70/30, dichloromethane/methanol 50/50, dichloromethane/methanol 30/70, and then methanol to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].C[N:20]([CH3:23])C=O>>[C:23]([C:3]1[CH:2]=[CH:9][C:6]([CH2:7][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(COc2ccc([N+](=O)[O-])c(C=O)c2)cc1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a stirred solution of 10.0 g (59.8 mmol) of 5-hydroxy-2-nitrobenzaldehyde and 12.3 g (62.8 mmol) of a-bromo-p-tolylnitrile in 50 ml of dry dimethyl-formamide was added 9.10 g (65.8 g) of anhydrous potassium carbonate. The mixture was warmed to 50° C. for 2 h and partitioned between water and ethyl acetate. The organic phase was washed with 1N sodium bicarbonate, water, brine, and dried over anhydrous magnesium sulfate. Concentration gave 13.8 g (82%) of 5-(4-cyanobenzyloxy)-2-nitrobenzaldehyde. 1H NMR (300 MHz, d6 -acetone) d 10.39 (1H, s, Ar-CHO), 8.23 (1H, d, J=9.0 Hz, O-Ar-H), 7.85 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.77 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.48 (1H, dd, J=9.0, 2.9 Hz, O-Ar-H), 7.43 (1H, d, J=2.9 Hz, O-Ar-H), 5.50 (2H, s, ArCH2O).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)CC)C>ClCCl>[CH3:15][C:13](=[CH2:14])[C:12]([O:8][C@@H:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[CH:9]([CH3:11])[CH3:10])=[O:16]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
In a 100 ml flask, equipped with a magnetic stirrer, 5.0 g of L-(−)-menthol and 3.51 g of methacryloyl chloride were added to a solution of 6.67 ml of triethylamine in 30 ml of dichloromethane at room temperature. The clear solution turned turbid after a few minutes (exothermic reaction). After 4 hours, the suspension was extracted with 25 ml of 0.5 N HCl, 25 ml of water, 25 ml of saturated aqueous NaHCO3 and 25 ml of brine to give a clear orange solution (after drying over Na2SO4). Concentrating at reduced pressure gave a light brown/orange oil, which was stored overnight at 4° C. Purification by column chromatography (eluens:ethyl acetate/heptane=1/4) gave 5.30 g (73.8%) of a colourless oil. 1H-NMR confirmed the expected structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>>[CH:25]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:18]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: OB(O)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Yield: 83.3 %

Procedure:
To 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride obtained by using the intermediate 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.86 g) described in Preparation Example 84 and cyclopropylboronic acid (5 g) and by the reaction and treatment in the same manner as in Preparation Example 82 was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (3.62 g).
Reaction SMILES: ClC(OC(Cl)C)=O.[CH2:8]([N:15]1[CH2:20][CH2:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:17]([F:29])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(CC1C2[C:37](=[N:38]C=CC=2)[NH:36]C=1)C>ClCCl.C1(C)C=CC=CC=1>[F:29][C:17]1[CH2:16][N:15]([CH2:8][C:9]2[C:10]3[C:37](=[N:38][CH:13]=[CH:12][CH:11]=3)[NH:36][CH:14]=2)[CH2:20][CH2:19][C:18]=1/[CH:21]=[CH:22]/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: FC1=C(/C=C/c2ccccc2)CCN(Cc2ccccc2)C1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: FC1=C(/C=C/c2ccccc2)CCN(Cc2c[nH]c3ncccc23)C1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
1-Chloroethyl chloroformate (0.048 ml, 0.44 mmol) was added dropwise to a solution of (E)-1-benzyl-3-fluoro-4-(2-phenylethenyl)-1,2,5,6-tetrahydropyridine (0.1002 g, 0.342 mmol) in dichloromethane (2 ml) at -8° C. The mixture was stirred at -8° C. to 0° C. for 1 hour, concentrated in vacuo, the residue redissolved in methanol (5 ml) and heated at reflux for fifteen minutes. The reaction mixture was evaporated and the residue partitioned between saturated aqueous potassium carbonate (25 ml) and dichloromethane (2×25 ml). The organic extracts were washed with brine (25 ml), combined, dried (MgSO4) and concentrated in vacuo. The residue and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.0606 g, 0.346 mmol) were suspended in toluene (5 ml) and the mixture stirred at reflux for 12 hours. The toluene was evaporated and the product purified by flash chromatography, eluting with dichloromethane/methanol/ammonia (120:8:1), to afford the title compound (0.0585 g, 51%). Recrystalisation from methanol gave buff needles, m.p. 218°-221° C. (dec.); δH (DMSO-d6) 2.35 (2H, m, tetrahydropyridinyl CH2), 2.64 (2H, m, tetrahydropyridinyl CH2), 3.16 (2H, br s, tetrahydropyridinyl CH2), 3.80 (2H, s, ArCH2N), 6.52 (1H, d, J 16.4Hz, CH=CHPh), 7.05 (1H, dd, J 7.8, 4.7Hz, 5-H), 7.14 (1H, d, J 16.4Hz, CH=CHPh), 7.23 (1H, m, ArH), 7.32 (2H, m, ArH), 7.42 (1H, s, 2-H), 7.48 (2H, m, ArH), 8.05 (1H, dd, J 7.8, 1.4Hz, 4-H), 8.20 (1H, dd, J 4.7, 1.4Hz, 6-H) and 11.51 (1H, br s, NH); m/z (CI+, NH3) 334 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH:23]=O)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:25](OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([C@H:11]2[CH2:12][CH2:13][C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[CH2:15][CH2:16]1)[CH2:21][CH2:22][CH:23]=[CH2:25]
Reactant: CCOCC
Reactant: O=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 5.19 g of methyl-triphenylphosphonium bromide in 80 ml of diethyl ether was treated with 1.55 g of potassium tert.butylate while gassing with nitrogen. The yellow suspension was stirred at room temperature for a further 45 minutes and then treated dropwise at 0° C. with a solution of 2.3 g of 4-[trans-4-[trans-4-(4-fluorophenyl)cyclohexyl]cyclohexyl]butyraldehyde. The reaction mixture was stirred at 0° C. for a further 2 hours and then diluted with 60 ml of water. The aqueous phase was separated and extracted twice with 60 ml of hexane each time. The combined organic phases were washed neutral with water, dried over sodium sulfate, filtered and concentrated. Chromatographic purification of the residue on silica gel with hexane gave 1.89 g of crude product. After two-fold recrystallization from acetone at -20° C. there were obtained 1.22 g of 1-[trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexyl]-4-fluorobenzene with m.p. (C--N) 65.7° C. and cl.p. (N--I) 129.7° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31]>CC(C)=O>[OH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]=[N:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1
Reactant: OCCCCCCCl
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(N=Nc2ccc(OCCCCCCO)cc2)cc1

Procedure:
22.3 g of 4'-cyano-4-hydroxyazobenzene and 14 g of dry potassium carbonate are dissolved in 100 ml of absolute acetone, a pinch of KI is added, and 15.3 g of 6-chlorhexan-1-ol are then added dropwise at the boil. The reaction mixture is refluxed for 6 days. The precipitated potassium chloride is filtered off under suction from the warm mixture, and the solution is evaporated down. 200 ml of CHCl3 are added to the dye obtained, and the chloroform solution is filtered off drom undissolved material, extracted by shaking four times with H2O and evaporated down. The crude product is recrystallized from 300 ml of acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C@H:8]2[CH2:11][C@H:10]([C:12]#[CH:13])[CH2:9]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH:21](=[O:23])[CH3:22]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C@H:8]2[CH2:9][C@H:10]([C:12]#[C:13][CH:21]([OH:23])[CH3:22])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: CC=O
Reactant: C#C[C@H]1C[C@H](Oc2ccc(OC)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(O[C@H]2C[C@H](C#CC(C)O)C2)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of {trans-3-(4-methoxyphenoxy)cyclobutyl }ethyne (6.40 g, 32.0 mmol) in THF (80 ml) at -78° C. under argon atmosphere was added n-butyllithium (23.7 ml, 38.0 mmol). The mixture was stirred for 0.5 h at the same temperature and then allowed to warm to -40° C. over 1 h. The mixture was recooled to -78° C., a solution of dry acetaldehyde (3.52 g, 80.0 mmol) in THF (20 ml) added to the mixture and the whole stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (100 ml) and the whole extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (200 ml), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography {SiO2, 500 g; hexane/ethyl acetate (3/1)} afforded 7.58 g (97%) of 4-{trans-3-(4-methoxyphenoxy)cyclobutyl }-3-butyn-2-ol as white solids: 1H NMR δ6.85-6.68 (m, 4H), 4.89-4.78 (m, 1H), 4.62-4.50 (m, 1H), 3.76 (s, 3H), 3.22-3.09 (m, 1H), 2.59-2.40 (m, 4H), 1.65 (s, 1H), 1.45 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][CH2:4][CH:5]=[CH2:6].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>O1CCCC1.C(OCC)(=O)C>[F:8][C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([C:2]([OH:7])([CH2:3][CH2:4][CH:5]=[CH2:6])[CH3:1])=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Reactant: C=CCCC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCC(C)(O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of hex-5-en-2-one (1.00 g, 10.2 mmol) in tetrahydrofuran (3 mL) was added to [4-(trifluoromethyl)phenyl]magnesium bromide (0.26 M solution in tetrahydrofuran, 50 mL, 13 mmol) at 0° C. After 15 minutes at 0° C., the reaction mixture was heated at 70° C. for 18 hours, then cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous ammonium chloride solution, with water, and with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in heptane) afforded the product as a dark gold oil. Yield: 1.86 g, 7.61 mmol, 75%. 1H NMR of crude product (400 MHz, CDCl3), characteristic peaks: δ 7.59 (br AB quartet, JAB=8 Hz, ΔνAB=19 Hz, 4H), 5.74-5.85 (m, 1H), 4.93-5.01 (m, 2H), 1.59 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH2:19])(C)(C)C.[C:21](O)([C:23]([F:26])([F:25])[F:24])=[O:22]>>[NH2:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:9][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:21](=[O:22])[C:23]([F:26])([F:25])[F:24]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Product: Nc1cc([N+](=O)[O-])ccc1CN(CC(=O)O)C(=O)C(F)(F)F

Procedure:
A solution of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (0.28 g, 1.0 mmol) was heated at 120° C. for 16 hours in TFA (5 mL). Concentration and chromatography on silica gel with methylene chloride and methanol (20:1) gave 0.3 g of [(2-amino-4-nitro-benzyl)-(2,2,2-trifluoro-acetyl)-amino]-acetic acid. Following a procedure analogous to Example 1848d, [(2-amino-4-nitro-benzyl)-(2,2,2-trifluoro-acetyl)-amino]-acetic acid was converted to 8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one: 1H NMR (300 MHz, CD3OD) δ 8.0 (m, 2H), 7.6 (dd, 1H), 4.98 (s, 1H), 4.57 (s, 2H), 4.53 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1.[CH2:17](C([Sn])=C(CCCC)CCCC)[CH2:18]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:17]=[CH2:18])=[CH:12][N:11]=1
Reactant: Fc1cccc(F)c1Nc1ccc(I)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(Nc2c(F)cccc2F)nc1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a mixture of (2,6-Difluoro-phenyl)-(5-iodo-pyridin-2-yl)-amine and Pd(PPh3)4 (approximately 10 mol %) in toluene (approximately. 80 mL/g) at room temperature was added tributylvinyltin (1.1 eq.). The reaction was placed under a N2 atmosphere and heated to 80° C. overnight. The solution was cooled, diluted with ethyl acetate (approximately 80 mL/g) and filtered through a pad of celite. The celite was washed with a further portion of ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo to give the crude reaction product as a yellow oil. Purification by column chromatography, using 10% ethyl acetate:hexane as eluant provided (2,6-Difluoro-phenyl)-(5-vinyl-pyridin-2-yl)-amine (Rf 0.14) in 66% yield.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.B(Br)(Br)Br>C(Cl)Cl>[CH:28]1([C:34]([N:9]2[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]3[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=3)[CH2:10]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccc(C2CNCc3cc(OC)ccc32)cc1
Agent: BrB(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCCCC1)N1Cc2cc(O)ccc2C(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinoline (0.103 g, 0.382 mmol, 1.0 eq., see Preparation 64) and triethylamine (0.107 ml, 0.764 mmol, 2.0 eq.) in CH2Cl2 (2 ml) was added to a vial containing cyclohexanecarbonyl chloride (0.084 g, 0.573 mmol, 1.5 eq.). The reaction mixture was stirred overnight at RT. To this mixture was added BBr3 as a 1.0M solution in CH2Cl2 (1.15 ml, 1.15 mmol, 3.0 eq.). The reaction mixture was stirred overnight at rt, then cooled to −78° C. and quenched with MeOH (1.5 ml). The reaction mixture was evaporated under a stream of nitrogen and purified by reverse phase HPLC (gradient elution 98:2 H20:0.1% TFA, then 2:98 MeCN:H2O). The exact yield was not determined.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[N:10]([CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[C:13]=[O:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN=C=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
β-Alanine tert-butyl ester hydrochloride (13.0, 71.6 mmol) in CH2Cl2 (240 mL) and saturated NaHCO3(aq) solution (240 mL) was degassed and the flask was cooled in ice water bath. Triphosgene (21.2 g, 71.6 mmol) was added in one portion under inert atmosphere at 0° C. The reaction stirred at 0° C. to RT over 2.5 hr. The reaction was diluted with water (500 mL) and poured into reparatory funnel. The layers separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude tert-butyl 3-iso cyanatopropionate (11.5 g) as a yellow liquid. This crude material was directly used for next reaction without purification. 1H NMR (300 MHz, CDCl3): δ 3.53 (t, 2H), 2.52 (t, 2H), 1.47 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:22][N:23]1[CH:27]=[C:26]([CH2:28][C:29]2[C:30](=[O:36])[NH:31][C:32](=[S:35])[NH:33][CH:34]=2)[CH:25]=[N:24]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH3:22][N:23]1[CH:27]=[C:26]([CH2:28][C:29]2[C:30](=[O:36])[N:31]=[C:32]([S:35][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=4)=[C:7]([CH:10]=3)[C:8]#[N:9])[NH:33][CH:34]=2)[CH:25]=[N:24]1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(C(F)(F)F)cn4)c(C#N)c3)nc2=O)cn1
Temperature: 60 °C
Yield: 42.1 %

Procedure:
To a solution of 5-(chloromethyl)-2-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzonitrile (97 mg, 0.310 mmol) and 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (76 mg, 0.341 mmol) in chloroform (2 mL) was added dropwise DIPEA (0.163 mL, 0.931 mmol) at 0° C. The mixture was heated at 60° C. for 2 h. Purification via reverse phase flash chromatography then afforded the title compound (65 mg, 42.0% yield). LCMS: rt=2.98 min, [M+H+]=499