Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:17]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
3-Bromomethylbenzonitrile (5.00 g, 25.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), phenol (2.40 g, 25.5 mmol) and potassium carbonate (10.6 g, 77 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (400 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (2×100 mL), dried (MgSO4) and evaporated in vacuo to afford 5.19 g (97%) 3-(phenoxymethyl)benzonitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].CCOCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:33]([NH:32][C:26]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=1[F:24])=[O:34]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)c2cc1OC
Yield: 46 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (214 mg) was dissolved in chloroform (5 ml), and 2,4-difluorophenyl isocyanate (180 μl) was then added to the solution. The mixture was allowed to react at 70° C. for 4 hr, and a large amount of ether was added to the reaction solution. The resultant precipitate was collected by suction filtration to give 146 mg (yield 46%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][C:7]=1[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[H][H]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: COC(=O)C=Cc1ccc(OCc2ccccc2)cc1CCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)(C)C
Yield: 36.7 %

Procedure:
To a solution of 3-[4-benzyloxy-2-(2-tert-butoxycarbonylamino-ethyl)-phenyl]-acrylic acid methyl ester (4.15 g, 10.1 mmol) in THF (100 mL) and MeOH (10 mL) was added 5% Pd—C (200 mg) in THF (10 mL). The resulting suspension was treated with hydrogen under balloon pressure for 18 h. The mixture was filtered through a pad of Celite and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexanes, 6/4) to afford the title compound (1.20 g, 34%). 1H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.57 (t, 2H, J=7.8 Hz), 2.77 (t, 2H, J=7.3 Hz), 2.88 (t, 2H, J=7.8 Hz), 3.33 (br s, 2H), 3.68 (s, 3H), 6.65 (br s, 1H), 6.67 (d, 1H, J=8.3 Hz), 7.02 (d, 1H, J=8.3 Hz). MS (ES+) m/z 324.1 [M+H]+.
Reaction SMILES: P(CCCC)(CCCC)CCCC.CCN(CC)CC.[CH2:21]([OH:26])[CH:22]([OH:25])[CH:23]=[CH2:24].Br[C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][CH:33]=1>CN(C=O)C.O>[OH:26][CH2:21][C:22](=[O:25])[CH2:23][CH2:24][C:32]1[CH:31]=[C:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28][CH:33]=1
Reactant: C=CC(O)CO
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: CCCCP(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(CCC(=O)CO)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a stirred solution of Pd (OAc)2 (75 mg, 0.34 mmol), nBu3P (136 mg, 0.67 mmol), and Et3N (442 mg, 4.37 mmol) in DMF (10 ml) was added 3-butene-1,2-diol (296 mg, 3.36 mmol) followed by methyl 3-bromophenylacetate (1.0 g, 4.37 mmol), and the reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by silica gel (25 g) column chromatography eluting with toluene/ethyl acetate (20:1) to give methyl 3-(4-hydroxy-3-oxobutyl)phenylacetate (193 mg, 24.4%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([NH:29][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]=1
Reactant: NCCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and 3-phenylpropylamine in DME. ES-MS m/e (%): 330 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:15]I>>[CH3:15][N:4]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1n[nH]c(-c2ccccn2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cn1nc(N)nc1-c1ccccn1

Procedure:
The 1-alkyl-3-amino-5-pyridinyl-1,2,4-triazole may be readily prepared from the corresponding 3-amino-5-pyridinyl-1,2,4-triazole under alkylating conditions. For instance, reaction of 3-amino-5-pyridinyl-1,2,4-triazole with sodium hydride followed by addition of methyl iodide yields the 1-methyl-3-amino-5-pyridinyl-1,2,4-triazole plus other isomers. Separation of the desired product may be readily accomplished by chromatography, distillation and the like.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:8](\[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)/[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: Cc1ccc(CC(=O)c2ccccc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(/C(=C\N(C)C)C(=O)c2ccccc2)cc1

Procedure:
A solution of 1-phenyl-2-p-tolylethanone (2 g, 9.5 mmol) and dimethylformamide dimethylacetal (4.5 g, 38.1 mmol) in DMF (30 ml) was heated at 75° C. for 24 hours. Solvents were removed under high vacuum to obtain the title compound as a yellow oil, which was used directly in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9](OC)OC)=[CH:4][CH:3]=1.ClS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[C:14]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[N:7][CH:8]=[CH:9]2
Reactant: COC(CNCc1ccc(Br)cc1)OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccc2cnccc2c1
Temperature: 45 °C
Reaction time: 10 h

Procedure:
To a stirred solution of N-(4-bromobenzyl)-2,2-dimethoxyethanamine (10 g, 0.037 mol) in CH2Cl2 (100 mL) was added ClSO3H (21.3 g, 0.18 mol) at −20° C. dropwise. The resulting reaction mixture was allowed to stir at 45° C. for 10 h. The resulting reaction mixture was diluted with CH2Cl2 and ice cold H2O, then neutralized with aqueous NaHCO3. The organic layer was separated and aqueous layer extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated at reduced pressure to get crude 6-bromoisoquinoline, which was purified by silica gel chromatography eluting with 5-15% EtOAc-hexanes to afford 6-bromoisoquinoline (0.9 g, 12%) as yellow liquid.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15](=[O:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClC1C=CC=CC=1Cl>[CH2:5]1[C:6]2[C:1](=[CH:7][C:8]3[C:13]([C:14]=2[C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)C#CCCCC/C=C/c1ccccc1
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1c2c(cc3ccccc13)CCCC2
Temperature: 300 °C
Reaction time: 0.83 h

Procedure:
To a 10 mL microwave irradiation vial equipped with a stir bar was added enyne 5l (0.042 g, 0.19 mmol) in o-dichlorobenzene (3.1 mL). The reaction was irradiated with stirring at 300° C. for 50 min in an Anton Parr Monowave 300 microwave reactor until complete by TLC. The reaction turned light brown in color. The reaction was then transferred to a vial and concentrated under high vacuum to yield naphthalene 6l as a brown oil (0.044 g, quant.).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][O:23][C:22]1=[O:26].C[Al](C)C.O>C1COCC1>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([NH:2][C:22](=[O:26])[C:21]([CH3:27])([CH3:20])[CH2:25][CH2:24][OH:23])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: CC1(C)CCOC1=O
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Agent: Br
Agent: C[Al](C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CCO)C(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 50 °C
Yield: 46 %

Procedure:
A mixture of 7-amino-4-bromo-9H-carbazole-1-carboxamide hydrobromide (Example 54-2, 500 mg, 1.299 mmol) and 3,3-dimethyldihydrofuran-2(3H)-one (222 mg, 1.948 mmol) in THF (10 mL) was treated with trimethylaluminum (2 M in toluene, 562 mg, 7.79 mmol) dropwise at rt. The mixture was heated at 50° C. for 1.5 h, cooled to rt and treated with water. The mixture was filtered through Celite and the solids were washed thoroughly with DCM and methanol. The filtrate was washed with water, dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from DCM to 10% ammonia-methanol-DCM) to provide 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide as a yellow solid (250 mg, 46%). Mass spectrum m/z 418, 420 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]12[CH2:8][C:6]([NH:9]C(=O)C)([CH2:7]1)[CH2:5]2)[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]12[CH2:8][C:6]([NH2:9])([CH2:7]1)[CH2:5]2)[CH3:2]
Reactant: CCOC12CC(NC(C)=O)(C1)C2
Agent: [Na+]
Agent: [OH-]
Product: CCOC12CC(N)(C1)C2

Procedure:
Hydrolysis of N-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2) with sodium hydroxide (or basic aqueous conditions) gives 3-ethoxybicyclo[1.1.1]pentan-1-amine (6) (Scheme 6).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH3:17]>C(OCC)(=O)C.CCCCCC.[C].[Pd]>[NH2:8][C:7]1[CH:6]=[C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=[C:3]([CH3:17])[C:2]=1[NH2:1]
Reactant: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(-c2ccccc2)cc(N)c1N
Yield: 99.7 %

Procedure:
[step 3] 4-Amino-3-methyl-5-nitrobiphenyl (100 mg, 0.44 mmol) obtained in step 2 was dissolved in ethanol-ethyl acetate (1/1, 4 mL), and the mixture was stirred in the presence of 10% palladium carbon (10 mg) under a hydrogen atmosphere at room temperature for 20 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3,4-diamino-5-methylbiphenyl (87 mg, 100%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C@H:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:14][CH:13]=2)[C:10](=[O:28])[CH2:9][CH2:8]1>ClCCl>[CH3:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]2[C:10](=[O:28])[CH2:9][CH2:8][C@H:7]2[CH2:6][NH:5][C:1](=[O:3])[CH3:2])=[CH:17][CH:16]=1
Reactant: CC(=O)Cl
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN)cc1
Solvent: ClCCl
Product: CC(=O)NC[C@@H]1CCC(=O)N1c1ccc(OCCCN2CCCC2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Acetyl chloride (0.51 ml, 0.72 mmol, 1.2 eq) is added to a cooled (ice bath) solution of (5S)-5-(aminomethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 113 (0.2 g, 0.6 mmol, 1 eq) in dichloromethane (12 ml). The mixture is stirred 2 hours at room temperature, washed with a saturated solution of sodium bicarbonate and with brine, dried over magnesium sulfate and concentrated under vacuum to give 0.158 g of yellow oil. The crude material is purified by two chromatographies over silicagel (first one: gradient dichloromethane/methanol/ammonia 100:0:0 to 88:12:1.2; second one: dichloromethane/methanol/ammonia 80:20:2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C:12]([NH:14][CH3:15])=O)=[CH:2]1.B.CSC>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:12][NH:14][CH3:15])=[CH:2]1
Reactant: CNC(=O)CC(c1ccccc1)c1c[nH]c2ccccc12
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CNCCC(c1ccccc1)c1c[nH]c2ccccc12

Procedure:
In an alternate procedure, 3-(1H-Indol-3-yl)-N-methyl-3-phenyl-propionamide (0.400 g) was reduced by refluxing overnight in THF (20 ml) with excess borane-dimethylsulfide to yield [3-(1H-Indol-3-yl)-3-phenyl-propyl]-methyl-amine, which was converted to an oxalate salt (mp 123.7-134.1° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:19])[C:13]4[CH:14]=[N:15][NH:16][C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:20]1([CH:28]=O)[C:21]([CH:26]=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C(OCC)(=O)C.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([N:19]4[CH2:28][C:20]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:26]4=[O:27])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccccc1C=O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1c1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.6 %

Procedure:
A mixture of 6-(1H-indol-4-yl)-1H-indazol-4-amine (100 mg, 0.403 mmol) and 1,2-benzenedicarbaldehyde (54 mg, 0.403 mmol) in ethyl acetate (1 ml) and acetic acid (0.25 ml) was stirred under a nitrogen atmosphere at room temperature for 3 h then overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with 5% sodium bicarbonate solution (10 ml). The phases were separated, and the aqueous phase was extracted with further ethyl acetate (20 ml). The combined organic extracts (which contained a small amount of insoluble solid) were dried over anhydrous sodium sulphate, filtered and evaporated to give a yellow foam. This was partially dissolved in ethyl acetate (20 ml) and pre-adsorbed on silica (1.5 g). This silica was then added to the top of a 20 g silica SPE cartridge. The cartridge was eluted on a Flashmaster (II) instrument using a gradient of 0-100% ethyl acetate in cyclohexane over 30 min. Appropriate fractions were combined and evaporated to give the title compound (20 mg) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>C1COCC1.CN(C=O)C.O>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:24]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1COc1cccc([N+](=O)[O-])c1C#N
Temperature: -20 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (0.86 g, 4 mmol) in dry THF (30 mL) was added at −20° C. NaH (0.32 g, 8 mmol) and the mixture was stirred 10 min at −20° C. and then 20 min at room temperature. The reaction mixture was then cooled to −20° C. and 2,6-dinitrobenzonitrile (0.772 g, 4 mmol) in dry THF (10 mL) and DMF (1 mL) was added dropwise over 15 min period. The solution was stirred under nitrogen at room temperature for 18 hours, diluted with water and extracted with EtOAc, the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by Biotage purification system (120 g Silicycle column, Hexane:EtOAc=3:2 as eluent) to give tert-butyl 2-((2-cyano-3-nitrophenoxy)methyl)piperidine-1-carboxylate (1.02 g, 70.6%). MS 262 [M+H-Boc]+.
Reaction SMILES: [CH2:1]1C(=O)N(Br)C(=O)C1.[F:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[N:19]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:26]([OH:28])=[O:27])[C:18](=[O:33])[CH:17]=2)=[C:12]([CH2:36][NH:37]C(OC)=O)[CH:11]=1>C(Cl)Cl>[C:36]([C:12]1[CH:11]=[C:10]([F:9])[CH:35]=[CH:34][C:13]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:26]([O:28][CH3:1])=[O:27])[C:18](=[O:33])[CH:17]=1)#[N:37]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3C#N)cc2=O)c1
Reaction time: 1.5 h

Procedure:
NBS (0.69 g, 3.85 mmol) was added to a solution of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from Step 4) (1.75 g, 3.85 mmol) in DCM (45 mL). After 1.5 h, solvent removed on rotary evaporator. Solid dissolved in EtOAc and hexane added, resulting in a solid precipitate. Solid filtered. Solid subsequently dissolved in DCM and washed with water. Organic layer dried over Na2SO4, filtered, and concentrated. Pale yellow solid dried in vacuo (1.47 g, 72%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].Cl.[CH3:25][N:26]([CH3:43])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][N:26]([CH3:43])[CH3:25])[CH:29]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(CN(C)C)c3)c(C)sc2n1
Temperature: 120 °C
Yield: 17 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzene sulfonamide (Example 61) (80 mg, 0.185 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL). N,N-Dimethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine hydrochloride (83 mg, 0.278 mmol), tetrakis(triphenylphosphine)palladium(0) (21.41 mg, 0.019 mmol) and potassium carbonate (51.2 mg, 0.371 mmol) were added and heated in a microwave at 120° C. for 15 min. Ethyl acetate (10 mL) was added and washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-20% 2M NH3 in MeOH in DCM, to give the title compound (15.3 mg). LCMS (A) m/z: 486 [M+1]+, Rt 0.92 min (acidic).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11].N1C=CC=CC=1.O.[Cl:23][CH2:24]Cl>>[Cl:23][CH2:24][C:14]1[CH:13]=[CH:12][C:9]2[C:10]([CH3:11])=[C:6]([CH3:5])[O:7][C:8]=2[CH:15]=1
Reactant: Cc1oc2ccccc2c1C
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1oc2cc(CCl)ccc2c1C
Yield: 76.4 %

Procedure:
Thionyl chloride (13.1 g, 0.11 mol) was added slowly to a stirred solution of 2,3-dimethylbenzofuran (18.0 g, 0.10 mol) and pyridine (8.3 cm3, 0.105 mol) in dichloromethane (170 cm3) at below 5° C., and the solution was heated under reflux for 3 hr. The solution was poured into water and separated, the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed to give 6-chloromethyl-2,3-dimethylbenzofuran (16.2 g, 0.078 mol, 76.4%). (Found: C, 67.76; H, 5.65; Cl, 18.21. C11H11ClO requires C, 67.87; H, 5.70; Cl, 18.22%) m.p. 63°-65° C. [ex petroleum ether (b.p. 60°-80° C.)].
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[H-].[Na+].[OH:18][C:19]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20]1.Cl>O1CCCC1.O>[CH3:25][O:24][C:22]([C:19]1([O:18][C:2]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=2)[CH2:21][CH2:20]1)=[O:23]
Reactant: COC(=O)C1(O)CC1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])c(OC2(C(=O)OC)CC2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methyl 4-fluoro-2-methyl-5-nitrobenzoate (43.0 g) was dissolved in tetrahydrofuran (300 ml), and thereto was added sodium hydride (55%, 9.60 g) at 0° C., and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of methyl 1-hydroxy-1-cyclopropanecarboxylate (22.0 g) in tetrahydrofuran (300 ml) at 0° C., and the mixture was further stirred at room temperature for 3 hours. The mixture was cooled to room temperature, and water (100 ml) was added to the reaction mixture. The mixture was neutralized by addition of 1N aqueous hydrochloric acid solution, and extracted twice with ethyl acetate (300 ml). The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resultant was purified by silica gel column (hexane/ethyl acetate=3:1) to give the title compound (58.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3I)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 59.2 %

Procedure:
The title compound was prepared by following the procedure as described for step-6 of Intermediate-26 by using methyl 4-(3-(2-chloro-6-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (0.100 g, 0.206 mmol), 3-(trifluoromethyl)aniline (0.041 g, 0.247 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (10.0 mL) to afford 0.075 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 7.19-8.03 (m, 9H), 8.25 (s, 1H), 10.36 (s, 1H), 12.65 (s, 1H); MS (m/z): 614.98 (M+H)+.