Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[CH:9]([CH2:10][CH:11]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:12]1)[C:8](=[O:42])[NH:7]2)=[O:5])C.C1COCC1.CO.O.[OH-].[Li+]>O>[C:29]([O:28][C:26]([NH:25][CH:15]1[C:14](=[O:33])[N:13]2[CH:9]([CH2:10][CH:11]([O:34][Si:35]([C:38]([CH3:40])([CH3:39])[CH3:41])([CH3:37])[CH3:36])[CH2:12]2)[C:8](=[O:42])[NH:7][C:6]2([C:4]([OH:5])=[O:3])[CH:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
To a solution of 14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester (1.5 g, 2.47 mmol) in a mixed solvent system of THF (4 mL), methanol (1 mL), and water (2 mL), was added powdered lithium hydroxide monohydrate (1.0 g, 50 mmol). The light yellow slurry was stirred at rt under N2 for 4 hours. The mixture was then concentrated in vacuo, and the residue partioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1 N HCl until reaching pH 4. This acidic solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried (MgSO4), filtered, and concentrated in vacuo to give 1.2 g (84%) of 14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as an off-white solid. 1H NMR (300 MHz, CD3OD) 0.12 (s, 6H), 0.89 (s, 9H), 1.23-1.64 (m, 17H), 1.70-1.87 (m, 1H), 1.90-2.49 (m, 6H), 3.70-3.80 (m, 1H), 3.83-3.90 (m, 1H), 4.28-4.36 (m, 1H), 4.47-4.55 (m, 1H), 4.65 (s, 1H), 5.30-5.39 (m, 1H), 5.53-5.62 (m, 1H); LC-MS (Method A, retention time: 3.69 min), MS m/z 580 (M++1).
Reaction SMILES: CN(C)CCNC.[CH2:8]([Li])[CH2:9][CH2:10]C.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(C=C)=[O:26]>O1CCCC1.CCCCCC>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:22]=[CH:21][C:18]2[CH:19]([OH:26])[O:20][CH:8]([CH:9]=[CH2:10])[C:17]=2[CH:16]=1
Reactant: C=CC=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: [Li]CCCC
Agent: CNCCN(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC1OC(O)c2ccc(C(F)(F)F)cc21
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of N,N,N′-trimethyl-1,2-ethanediamine (4.76 mL, 37.4 mmol) in tetrahydrofuran (150.00 mL) was added a 1.6 M solution of n-butyllithium in hexane (25.7 mL) at −40° C. The colorless solution became light yellow. The cold bath was removed and the reaction stirred for 30 min while warming to −15° C. The reaction was rechilled at −40° C. and 4-trifluoromethylbenzaldehyde (5.00 mL, 37.4 mmol) was added. The reaction was stirred at −50° C. for 35 min before a second addition of a 1.60 M solution of n-butyllithium in hexane was carried out. The reaction was allowed to warm to −25° C. and maintained at −25° C. for 2 h at which time acrolein (2.75 mL, 41.2 mmol) was added. The reaction mixture was stirred overnight and quenched by addition of 30 mL of 6 N HCl aqueous solution. The organic layer was separated and the aqueous phase was extracted with EtOAc twice (2×30 mL). The combined extracts were washed with brine, dried over Na2SO4, evaporated in vacuo and purified by flash chromatography to give the desired product (2.4 g, 28% yield). LC-MS [M+1]=231.2.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)=[O:19])=[CH:14][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5ccccc54)cc3)cc2C(F)(F)F)CC1

Procedure:
is obtained analogously to the method as described in Example 1 but using (4-benzoimidazol-1-yl-phenyl)-acetic acid instead of (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine instead of 3′-bromo-2-trifluoromethyl-biphen-4-ylamine as a starting material (see WO 03/099771). ES-MS: 508.0 [M+H]+; single peak at tR=2.84 min (System 1); Rf=0.10 (CH2Cl2/MeOH+1% NH3aq, 9:1). Starting material is prepared as follows: Step 2.1: (4-Benzoimidazol-1-yl-phenyl)-acetic acid
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[C:25]([F:28])([F:27])[F:26])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Fc1ccc2c(c1)C(C(F)(F)F)NCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(F)cc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]([O:3][CH:4]=[CH2:5])=[CH2:2].[CH3:6][O:7][C:8](=[O:15])[CH2:9][C:10]1CCCC=1.C([O-])(=O)C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:6][O:7][C:8](=[O:15])[CH2:9][CH:10]1[CH2:2][CH:1]2[O:3][CH:4]2[CH2:5]1
Reactant: COC(=O)CC1=CCCC1
Reactant: C=COC=C
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1CC2OC2C1
Temperature: 35 °C
Yield: 66.5 %

Procedure:
Preparation of a vinyl ether compound having the formula: ##STR51## A) 43.46 g (0.31 mol) of cyclopentenylacetic acid methyl ester are dissolved in 80 ml of chloroform. After the addition of 4 g of sodium acetate, 82.51 g of a 40% solution of peracetic acid in acetic acid are added dropwise thereto, with stirring, the temperature being maintained at about 35° C. The reaction mixture is then stirred for a further 5 hours at 35° C. The reaction mixture is extracted with 5% sodium hydrogen carbonate solution and then twice with water. The organic phase is then separated off and dried and residual peroxide is destroyed with sodium sulfite. After distillation of the organic phase there are obtained 32.3 g of 3,4-epoxycyclopentylacetic acid methyl ester (66.5% of theory).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:16])[CH2:5]1.C([N:36]1[CH:40]=[C:39]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)[N:38]=[CH:37]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(Cl)[Cl:75]>>[ClH:75].[C:48]([C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C:39]2[N:38]([CH2:2][CH2:3][CH:4]3[CH2:9][CH2:8][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6](=[O:16])[CH2:5]3)[CH:37]=[N:36][CH:40]=2)=[CH:47][CH:46]=1)#[N:49]
Reactant: ClCCl
Reactant: O=C1CC(CCO)CCN1c1ccccc1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: N#Cc1ccc(Cc2cncn2CCC2CCN(c3ccccc3)C(=O)C2)cc1
Temperature: -78 °C

Procedure:
The product from Step F (1 eq) and the product from Example 1, Step E (1 eq) were dissolved in methylene chloride containing diisopropylethylamine , cooled to -78° C. under argon and treated with trifluoromethane sulfonic anhydride as described in Example 1, Step F. After methanolysis, the title compound was isolated by chromatography on silica gel.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:12](=[O:41])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:19][C:20](=[O:32])[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])C1C=CC=CC=1>C(O)(=O)C.O.[Pd]>[C:49]([O:48][C:46](=[O:47])[NH:45][CH2:44][CH2:43][CH2:42][C@H:11]([NH2:10])[C:12](=[O:41])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:19][C:20](=[O:32])[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)NCCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
290 mg (0.390 mmol) of benzyl((1S,8S)-8-[(tert-butoxycarbonyl)amino]-1-{3-[(tert-butoxycarbonyl)amino]propyl}-17,17-dimethyl-2,10,15-trioxo-16-oxa-3,11,14-triazaoctadec-1-yl)carbamate (Example 226A) are dissolved in 10 ml of a 4/1 glacial acetic acid/water mixture. 75 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated under atmospheric pressure for 15 h. The reaction mixture is filtered through a Millipore filter and the filtrate is concentrated and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:35]=[CH:34][C:17]([C:18](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1.[N:36]1[CH:41]=[CH:40]C=[CH:38][CH:37]=1>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O-:9])=[O:8])=[CH:10][CH:11]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:17]2[CH:34]=[CH:35][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:24][CH:23]=1.[CH2:37]([NH+:36]([CH2:11][CH3:3])[CH2:41][CH3:40])[CH3:38]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: c1ccncc1
Product: CC[NH+](CC)CC
Product: COc1ccc(C(OCc2ccc(C(=O)[O-])cc2)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
A solution of commercial 4-(hydroxymethyl)benzoic acid (1.52 g, 10.0 mmol) in pyridine (50 mL) is treated with 4,4′-dimethoxytrityl chloride (3.73 g, 11.0 mmol) overnight at room temperature and concentrated to an oil in vacuo. The residue is dissolved in a mixture of MeOH and CH2Cl2 (95:5, v/v; 200 mL) and washed with 2 M aqueous triethylammonium acetate (5×20 mL). The organic solution is evaporated, re-dissolved in CH2Cl2, dried over Na2SO4, and evaporated to give crude triethylammonium 4-[[(4,4′-dimethoxytrityl)oxy]methyl]-benzoate in quantitative yield (1016 mg).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[O:26][C:27]=1[CH3:28]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:25]1[O:26][C:27]([CH3:28])=[C:23]([CH2:22][N:12]2[C:13]3[C:9](=[C:8]([CH3:16])[C:7]([CH2:6][CH:5]([O:17][CH2:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)[N:24]=1
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-4-methyl-1H-indol-5-yl}-2-ethoxy-propionic acid as yellow solid.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[N:10]=[CH:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: [H][H]
Reactant: Cc1ccccc1Cc1cn(Cc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1Cc1c[nH]cn1

Procedure:
12.3 g of N-benzyl-4-(2'-methylbenzyl)imidazole are dissolved in 100 ml of ethanol. 0.3 g of 10% palladium-on-carbon is added and the reaction mixture is stirred vigorously at 70° C. in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is cooled and filtered. Subsequent treatment as described in Example 54 above affords the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32]C[CH2:30][CH2:29]1.C([N:37](C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:37]([CH2:18][CH2:17][CH2:16][C:14]2[O:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=2)[CH2:30][CH2:29]1
Reactant: Clc1ccccc1N1CCCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4Cl)CC3)on2)cc1OC
Yield: 81.9 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (34.0 mg, 0.13 mmol), (2-chlorophenyl)piperidine HCl (25.2 mg, 0.11 mmol), and diisopropylethyl amine (18.8, 0.11 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (68.7 mg, 0.32 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22 hr and followed the same processes as in Example 1 to obtain 39.8 mg (82.0%) of the target compound.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30](Cl)[CH:31]=1)[CH:27]=O>>[Br:23][C:24]1[CH:31]=[CH:30][C:29]([Cl:1])=[C:26]([CH:25]=1)[CH2:27][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: O=Cc1cc(Cl)cc(Br)c1
Reactant: Cl
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Br)ccc4Cl)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 3-bromo-5-chlorobenzaldehyde (43.7 mg, 0.199 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow oil (76 mg) that was used without any further purification.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]1.C(N(CC)C(C)C)(C)C>CN1C(=O)N(C)CC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[F:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]2)=[C:3]2[CH:11]=[CH:10][NH:9][C:4]2=[N:5][CH:6]=1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC(=O)C1CCCN(c2c(F)cnc3[nH]ccc23)C1
Temperature: 200 °C
Yield: 10.8 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg), 3-piperidinecarboxamide (45 mg) and N,N-diisopropylethylamine (30 μL) in DMI (0.4 mL) was heated in the microwave reactor (200° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave 1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-piperidinecarboxamide (5 mg) as a pale brown solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[CH3:20][C:21]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:21]=2[CH3:20])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(Oc2ccc(C=O)cc2)c1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: C=CCOc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Yield: 82 %

Procedure:
The product from Example 61C and 2-methyl-3-nitroaniline were processed as described in Example 6A to provide the title compound (7.20 g, 82%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:17]2[C:16]([NH:15][S:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:1]=[CH:2][CH:3]=[CH:4]4)(=[O:13])=[O:12])=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:18]=2)=[CH:33][CH:34]=1)#[N:39]
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3cccc4cccnc34)c(Oc3ccc(C#N)cc3)n2)cc1
Yield: 101.3 %

Procedure:
8-Quinoline sulfonyl chloride (0.172 g, 0.76 mmol) was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.25 g, 0.76 mmol). Using other reagents and reaction conditions as mentioned in Example 1(c) afforded 0.4 g of the required product. 1H NMR (DMSO-d6): δ 6.92 (1H, d), 7.11 (1H, d), 7.18 (2H, d), 7.25 (1H, d), 7.51 (2H, d), 7.56 (1H, dd), 7.66 (1H, t), 7.74 (2H, d), 7.80 (2H, m), 7.98 (1H, d), 8.20 (2H, m), 8.38 (1H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:21]#[N:22])=[C:13]([CH:20]=1)[C:14](N(OC)C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([Mg]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[C:14]([C:13]1[CH:20]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([O:23][CH3:24])=[CH:11][C:12]=1[C:21]#[N:22])(=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(C#N)c(C(=O)N(C)OC)cc1OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C#N)c(C(=O)c2ccccc2)cc1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
To a mixture of 5-benzyloxy-2-cyano-4,N-dimethoxy-N-methylbenzamide (reference example 6-2) (203 mg) and tetrahydrofuran (3.1 mL) was added phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.7 mL) under ice-bath cooling. The mixture was stirred for 1.5 hours. Phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.3 mL) was added to the mixture. After stirring under ice-bath cooling for 50 minutes, the mixture was stirred at room temperature overnight. Phenylmagnesium bromide (1.08 mol/L tetrahydrofuran solution, 0.35 mL) was added to the mixture. After stirring at 0° C. for 1.5 hours, to the mixture were added a saturated aqueous solution of ammonium chloride, 1 mol/L hydrochloric acid and ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water and brine successively, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-30% ethyl acetate/hexane, gradient elution) to give the title compound (112 mg).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4]C(OCC)=O.[N+:15]([O-])([OH:17])=[O:16].C(=O)(O)[O-].[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:3]=1[OH:4]
Reactant: CCOC(=O)Oc1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(O)c(F)cc1F
Temperature: 15 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of ethyl 2,4-difluorophenoxycarboxylate (3.27 g, 16.2 mmol) in concentrated H2SO4 (11 mL) at 0° C. was added fuming HNO3 (1.1 mL) dropwise, maintaining the internal temperature between 10 to 20° C. After stirring for 1 h, the mixture was poured over ice water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×40 mL), dried over MgSO4, and concentrated in vacuo. The residue was dissolved in MeOH (50 mL), and sodium bicarbonate (2.72 g, 32.3 mmol) was added. The resultant mixture was stirred at room temperature for 64 h and the solid was filtered. The filtrate was concentrated and the residue was taken up in H2O (100 mL). The pH was adjusted to 5 with the addition of conc. HCl, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×40 mL), dried over MgSO4, and evaporated under reduced pressure to give 2,4-difluoro-5-nitrophenol as a yellow solid (2.35 g, 13.4 mmol; 83% yield). 1H-NMR (DMSO-d6) δ 10.88 (s, 1H), 7.70 to 7.61 (m, 2H),
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=1)=O.[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:43]=1[C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:41][C:42]1[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:43]=1[C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH2:15][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=2)=[CH:51][CH:50]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (89 mg, 0.42 mmol) was added to a DCE solution (1 mL) of ethyl 3-(5-(2-formyl-4-methoxyphenyl)picolinamido)propanoate (100 mg, 0.28 mmol), 2′,4′-dichloro-[1,1′-biphenyl]-4-amine (100 mg, 0.42 mmol), and AcOH (0.02 mL, 0.28 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11]CC)=O)=[N:4][CH:3]=1.[NH3:14]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([NH2:14])=[O:11])=[N:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1ncc(Br)c(=O)[nH]1
Solvent: CCO
Product: NC(=O)c1ncc(Br)c(=O)[nH]1
Temperature: 50 °C

Procedure:
To a solution of ethyl 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4, 0.2 g, 0.81 mmol) in ethanol (4 mL), liquid ammonia (4 mL) was added dropwise at room temperature. The reaction mixture was heated at 50° C. for 16 h. TLC showed consumption of starting material. Solvent was removed under reduced pressure and the residue was treated with methanol (1 mL) and filtered. The solid was washed with diethyl ether and dried under reduced pressure to afford 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxamide (5) as off white solid. Yield: 0.14 g, 76%; MS (ESI) m/z 218.87 [M+1]+.