Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10](N)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].Cl.N([O-])=[O:22].[Na+].S(=O)(=O)(O)O>O>[OH:22][C:9]1[CH:8]=[C:7]2[C:12]([C:13]3[CH:5]=[CH:4][C:3]([CH2:16][C:17]([OH:19])=[O:18])=[CH:2][C:14]=3[CH2:6]2)=[CH:11][CH:10]=1
Reactant: Cc1c(CC(=O)O)ccc2c1Cc1cc(N)ccc1-2
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)Cc1cc(O)ccc1-2
Reaction time: 2 h

Procedure:
A solution of 14.5g. of methyl 7-aminofluorene-2-acetic acid in 380ml. of water containing 14ml. of concentrated hydrochloric acid is cooled to 2° and a solution of 3.63g. of sodium nitrite in 15ml. of water added dropwise while stirring. The diazonium solution is added over a 1 hour period while stirring to a refluxing solution of 1.1 liters of water containing 18ml. of sulfuric acid. The mixture is cooled and the solid collected by filtration. The solid is refluxed with 120ml. of 10% aqueous potassium hydroxide solution for 2 hr., and treated with Darco. The suspension is filtered, acidified with hydrochloric acid and the solid collected by filtration, dried, and crystallized from acetonitrile to give 9.4g. of the title compound, 240°-241°d.
Reaction SMILES: C(O)(=O)C.CO.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[N:16]1[C:20](=[O:21])[CH2:19][C:18]([NH:22][C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=3)[C:26]([Cl:39])=[CH:25][C:24]=2[Cl:40])=[N:17]1>[Fe].O>[Cl:15][C:10]1[CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]([Cl:7])[C:9]=1[N:16]1[C:20](=[O:21])[CH2:19][C:18]([NH:22][C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([NH2:36])=[CH:34][CH:35]=3)[C:26]([Cl:39])=[CH:25][C:24]=2[Cl:40])=[N:17]1
Reactant: O=C1CC(Nc2cc(Oc3ccc([N+](=O)[O-])cc3)c(Cl)cc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Oc2cc(NC3=NN(c4c(Cl)cc(Cl)cc4Cl)C(=O)C3)c(Cl)cc2Cl)cc1
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
In a solvent mixture of 100 ml of glacial acetic acid, 10 ml of methanol and 10 ml of water was dispersed 10 g of 1-(2,4,6-trichlorophenyl)-3-[2,4-dichloro-5-(4-nitrophenoxy)anilino]-2-pyrazolin-5-one prepared as described in Step (1) above. To the dispersion was added 10 g of iron powder with heating under stirring over a 10 minute period. The reaction mixture was poured into 1 l of water and the precipitate crystallized out was recovered by filtration to obtain 8 g of the desired compound.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:47])[CH2:45][OH:46])[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:47])[CH2:45][OH:46])[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC(CO)Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CC(CO)Cn1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75. Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:6](=[O:19])[N:5]([CH2:20][CH3:21])[C:4]=2[N:3]=1.[F:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25](=[N:27]O)[NH2:26]>CS(C)=O>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[O:18][N:26]=[C:25]([C:24]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:23]=4[F:22])[N:27]=3)[C:6](=[O:19])[N:5]([CH2:20][CH3:21])[C:4]=2[N:3]=1
Reactant: CCn1c(=O)n(CCCCC(=O)O)c(=O)c2[nH]c(Cl)nc21
Reactant: NC(=NO)c1ccc(F)cc1F
Solvent: CS(C)=O
Product: CCn1c(=O)n(CCCCc2nc(-c3ccc(F)cc3F)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (0.05 g, 0.16 mmol) in DMSO (1 ml) was treated with CDl (0.029 g, 0.18 mmol) and the mixture stirred at room temperature for 1 h. Subsequently, the mixture was treated with 2,4-difluorobenzamidoxime (0.03 g, 0.18 mmol) and then heated to 120° C. for 30 min. The product was purified from the crude mixture using MDAP. Product-containing fractions were evaporated using a stream of nitrogen and the resulting colourless gum triturated in ether and dried to reveal the title compound as a white solid (50 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: C#CCCc1nc2ccccc2s1
Product: Fc1ccc(C#CCCc2nc3ccccc3s2)nc1
Yield: 47.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoro-pyridine (103 mg, 0.59 mmol) and 2-but-3-ynyl-benzo[d]thiazole (110 mg, 0.59 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 78 mg (0.28 mmol, 47%) of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=O)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C.O.[NH2:22][NH2:23]>C(O)CC>[CH3:1][N:2]([CH2:7][C:8](=[N:22][NH2:23])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)N(C)CC(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCCO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)N(C)CC(=NN)c1ccc(Cl)cc1
Yield: 70.7 %

Procedure:
101 g (418 mmol) of 2-(N-methyl-N-(methoxycarbonyl)-amino)-4′-chloroacetophenone was dissolved in 600 ml of warm 1-propanol. To this mixture was added 4.85 g (80 mmol) of acetic acid and 60.9 g (1218 mmol) of hydrazine monohydrate. The mixture was refluxed for two hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over magnesium sulfate, filtering, and reconcentrating in vacuo, there was obtained 75.6 g of the title compound, an oil.
Reaction SMILES: [C:1]([C:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])([O:3]C)=[O:2].[OH-].[K+]>CO.O1CCCC1.O>[C:1]([C:5]1[CH2:10][C:9]([C:24]#[N:25])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:12]=2)[CH2:8][CH2:7][C:6]=1[O:26][CH2:27][O:28][CH3:29])([OH:3])=[O:2]
Reactant: COCOC1=C(C(=O)OC)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCOC1=C(C(=O)O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Yield: 53.7 %

Procedure:
A solution of 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene (0.5 g, 1.25 mmol) and potassium hydroxide (0.21 g, 3.75 mmol) in methanol (13 mL), tetrahydrofuran (5 mL) and water (7.5 mL) under an argon atmosphere was heated at 65° C. for 3 h. The mixture was partitioned between methylene chloride and acidic water, was extracted twice, the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 5% methanol/chloroform, provided an oil (0.26 g, 54%).
Reaction SMILES: F.N1C=CC=CC=1.[Si]([O:15][CH:16]([C:18]1[CH:19]=[C:20]2[C:25](=[N:26][C:27]=1[CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:24]([C:33]([NH:35][C:36]1[CH:41]=[C:40]([NH:42][CH2:43][CH2:44][O:45][CH3:46])[C:39]([C:47]#[N:48])=[CH:38][N:37]=1)=[O:34])[CH2:23][CH2:22][CH2:21]2)[CH3:17])(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[C:47]([C:39]1[C:40]([NH:42][CH2:43][CH2:44][O:45][CH3:46])=[CH:41][C:36]([NH:35][C:33]([N:24]2[C:25]3[C:20](=[CH:19][C:18]([CH:16]([OH:15])[CH3:17])=[C:27]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:22][CH2:23]2)=[O:34])=[N:37][CH:38]=1)#[N:48]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)O[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)O)c(C(OC)OC)nc32)ncc1C#N
Reaction time: 18 h

Procedure:
Pyridine hydrofluoride (0.130 ml, 1.012 mmol) was added to a suspension of (racemic) 6-(1-((tert-butyldimethylsilyl)oxy)ethyl)-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 184, 296 mg, 0.506 mmol) in THF (2.5 ml) and stirred for 18 h. The reaction mixture was poured into saturated aqueous NaHCO3 and DCM was added. Phases were separated and the water phase was back extracted with DCM (3×). Organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with MeOH (0-4%) in DCM to yield the title compound as a colorless solid. (UPLC-MS 3) tR 0.90 min, ESI-MS 471.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 13.62 (s, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.53 (s, 1H), 6.92 (t, 1H), 5.45 (s, 1H), 5.23-5.16 (m, 2H), 3.98-3.88 (m, 2H), 3.53 (t, 2H), 3.41-3.31 (m, 8H), 3.30 (s, 3H), 2.89-2.83 (m, 2H), 1.95-1.86 (m, 2H), 1.30 (d, 3H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OCCNCCO
Product: OCCN(CCO)Cc1ccc(Br)cc1

Procedure:
2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (22.5 g,, 150 mmol). and 4-bromobenzyl bromide (25 g, 100 mmol). Yield 33.66 g, (99%); yellow oil; MS: 273.8 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[N:6]=1)[OH:4])#[N:2].[C:20]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[N:25]=1)[OH:23])#[N:21].[Cl:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1[NH:49][CH:50]([CH:54]([CH3:56])[CH3:55])[C:51](O)=[O:52]>>[Cl:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1[NH:49][CH:50]([CH:54]([CH3:56])[CH3:55])[C:51]([O:4][CH:3]([C:1]#[N:2])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[N:6]=1)=[O:52].[Cl:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1[NH:49][CH:50]([CH:54]([CH3:56])[CH3:55])[C:51]([O:23][CH:22]([C:20]#[N:21])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[N:25]=1)=[O:52]
Reactant: N#CC(O)c1cccc(Oc2ccccc2F)n1
Reactant: Cc1ccc(Oc2cccc(C(O)C#N)n2)cc1C
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OC(C#N)c1cccc(Oc2ccccc2F)n1
Product: Cc1ccc(Oc2cccc(C(C#N)OC(=O)C(Nc3ccc(C(F)(F)F)cc3Cl)C(C)C)n2)cc1C

Procedure:
The alcohol, cyano[6-(3,4-dimethylphenoxy)-2-pyridyl]methanol and cyano[6-(2-fluorophenoxy)-2-pyridyl]methanol, is reacted with the acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid to yield cyano[6-(3,4-dimethylphenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate and cyano[6-(2-fluorophenoxy)-2-pyridyl]methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([O:20]C)[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([OH:20])[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1
Reactant: CCOC(=O)C=Cc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 68 h
Yield: 83.1 %

Procedure:
A solution of 8-Chloro-4-[2-(ethoxycarbonyl)ethenyl]-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.1009 g) in tetrahydrofuran (2.3 mL) was treated with a solution of lithium hydroxide monohydrate (0.0126 g) in tetrahydrofuran (2.3 mL) and water (0.5 mL) at room temperature. The solution was stirred at room temperature under argon for 68 hours. It was then added to 0.05N hydrochloric acid (10 mL). The resulting solid was filtered off, washed with water, and air-dried to give a light tan solid (0.0803 g). The solid was dissolved in hot ethanol (5 mL). The solution was filtered and treated with water (2 mL). The crystals were filtered off at room tempeature, washed with aqueous ethanol (1:1, v:v) and dried under vaccum to give a light tan solid (0.054 g); mp 177.5°-178.4° C.; 1H NMR (d6 -DMSO) 7.74 (d,1, J=16) 6.74 (d,1, J=16) for trans olefin protons; MS: m/z=276 (base peak), 322 (M+1). Analysis for C15H12ClNO5 : Calculated: C, 56.00; E, 3.78; N, 3.99; Found: C, 56.55; H, 3.78; N, 3.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(Cl)(Cl)Cl>C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[S:22][C:13]=12
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C#N)cnc3cc(C#C[Si](C)(C)C)sc23)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), (trimethylsilyl)acetylene (237 μL, 1.67 mmol), 12.5 mg of tetrakis(triphenylphosphine)palladium(0) and 5 mg of copper(I) iodide in 3.5 mL of triethylamine and 12 mL of benzene is heated at reflux for 20 hours. The mixture is cooled to room temperature and 50 mL of chloroform are added. The mixture is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered through a celite pad and concentrated in vacuo. The resulting brown solid is suspended in diethyl ether. The solids are collected by filtration and washed with diethyl ether to yield 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(trimethylsilyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 169–171° C.; 1H NMR (CDCl3) δ 0.26 (s, 9H), 3.88 (s, 3H), 6.79 (s, 1H), 6.89 (s, 1H), 7.51 (s, 1H), 7.56 (s, 1H), 8.65 (s, 1H); MS 444.1, 446.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:25]=[N+:26]=[N-:27].[Na+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[NH:27][N:26]=[N:25][N:14]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A mixture of 285 g of the nitrile, 262.5 g triethylamine hydrochloride and 124 g of sodium azide in 1.5 L of DMF under nitrogen was stirred under reflux for 18 hrs. The reaction mixture was cooled to room temperature, poured into 4 L of cold water and acidified with 3N HCl. The resulting white solid was collected, washed with water and dried at 60° C. in vacuo for 48 hrs to give 337 g of 5-(4-benzyloxyphenyl)tetrazole.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:13]=[C:12]2S)[CH:5]=1.[N+]([O-])(O)=O.N([O-])=O.[Na+].[OH-].[Na+]>O.CC(O)=O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:23])=[O:2])=[CH:5][C:6]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12]1
Reactant: COC(=O)c1ccc(C)c(-n2cc(-c3cccnc3)nc2S)c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1ccc(C(=O)O)cc1-n1cnc(-c2cccnc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a suspension of 85 mg (0.261 mmol) of 3-(2-mercapto-4-pyridin-3-yl-imidazol-1-yl)-4-methyl-benzoic acid methyl ester in 1.8 mL of water was added 0.68 mL of concentrated HNO3 and 2 mg of NaNO2. After 2 h, the mixture was cooled to 0° C. and 4N NaOH was added until the pH reached about 10. The mixture was stirred for 30 min then HOAc was added until the pH reached about 6. The resulting precipitate was filtered, washed with water and dried to provide 16 mg (0.057 mmol, 22%) of the title compound.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.N1C(C)=CC=CC=1C.[F:24][C:25]([CH3:29])([CH3:28])[CH2:26]O>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:26][C:25]([F:24])([CH3:29])[CH3:28])(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(F)CO
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(F)COS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Trifluoromethanesulfonic anhydride (12.06 ml, 71.24 mmol), followed by 2,6-lutidine (11.42 ml, 81.42 mmol) were added to a solution of 2-fluoro-2-methylpropan-1-ol (6.25 g, 67.85 mmol) in DCM (146 ml) at −10° C. The reaction was stirred for 1 hr. then washed with 2N HCl (2×100 ml) and saturated NaHCO3 solution (2×100 ml). The organic phase was then cried over Na2SO4 and concentrated to give 2-fluoro-2-methylpropyl trifluoromethanesulfonate (12.89 g, 85%) as a red oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:14]C(OC(C)(C)C)=O)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:55]([C:62]1[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.Cl>O1CCOCC1.CN(C=O)C>[NH2:14][CH:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([NH:66][C:65]1[CH:64]=[CH:63][C:62]([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:68][CH:67]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
A flask was charged with 3-benzyloxy-2-tert-butoxycarbonylaminopropionic acid (5.0 g, 16.9 mmoles), HATU (7.0 g, 18.6 mmoles) and DMF (5 mL). DIEA (8.8 mL, 50.7 mmoles) was added and the mixture was stirred for 15 minutes. 4-Phenoxyaniline (3.4 g, 18.6 mmoles) was added and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined extract was washed sequentially with 5% lithium chloride (3×10 mL), 1N sodium bicarbonate (2×10 mL), 5% citric acid (2×10 mL), deionized water (2×10 mL) and then brine (1×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized from methanol to afford a white solid. The solid was combined with 4N hydrogen chloride in dioxane (25 mL). The mixture was stirred at ambient temperature for 18 hours. Volatiles then were removed under rotary evaporation. The resultant oil was partitioned between 1N sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extract was washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude was recrystallized from methanol to give 2-amino-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (2 g, 5.47 mmoles, 33% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 9.55 (s, 1H), 7.60-7.50 (m, 2H), 7.40-7.27 (m, 5H), 7.08 (t, 1H), 7.01-6.95 (m, 3H), 4.57 (t, 2H), 3.85-3.70 (m, 3H), 1.97 (2, 2H). MS (D) for C22H22N2O3. found 363.0 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20][C@@H:21]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].O.Br[C:39]#[N:40]>C(Cl)Cl.[Cl-].[Na+].O>[C:39]([N:25]1[CH2:24][CH2:23][CH:22]([C@H:21]2[N:16]3[N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:28]([C:29]([NH2:31])=[O:30])=[C:17]3[NH:18][CH2:19][CH2:20]2)[CH2:27][CH2:26]1)#[N:40]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC[C@H]2C1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCC([C@@H]2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of (S)-2-(4-phenoxyphenyl)-7-(piperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (417 mg, 1 mmol) in DCM (20 mL) was added NaHCO3 (168 mg, 2 mmol) and water (5 mL), followed by BrCN (127 mg, 1.2 mmol). The mixture was stirred at RT for 16 h. To the mixture was added DCM (50 mL) and brine (20 mL). The organic phase was further washed with brine (100 mL), dried over Na2SO4. Concentrated and purified by Pre-TLC (DCM/MeOH, 50/1) to afford 330 mg (75%) of white solid. MS (ESI) m/e [M+1]+ 443.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9](=[C:16]2SCS2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24][CH2:23]1.[NH2:30][NH2:31]>C1(C)C=CC=CC=1>[OH2:20].[OH2:20].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:31][N:30]=[C:16]([N:28]([CH3:29])[CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1ccc(Cl)cc1
Reactant: NN
Reactant: CNC1CCN(C)CC1
Solvent: Cc1ccccc1
Product: CN1CCC(N(C)c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Product: O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone (3.2 g, 0.01 mol; prepared as set forth in Step 1 of Example A-341) and 1-methyl-4-methylaminopiperidine (3.8 g, 0.03 mol) in 30 mL of toluene refluxed for six hours under nitrogen. The mixture was cooled and solvent was removed under vacuum. The residue was dissolved in dry tetrahydrofuran (30 mL) and anyhydrous hydrazine (650 mg, 0.02 mol) was added. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The resulting precipitate was filtered and warmed in methanol and a few drops of concentrated ammonium hydroxide. The mixture was filtered hot and the filtrate blown down to half the volume. As the filtrate cooled, a product separated and was filtered to give 395 of pure N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-N,1-dimethyl-4-piperidinamine, dihydrate, m.p. 260–261° C. Anal. Calc'd for C21H24ClN5.2H2O: C, 60.35; H, 6.75; N, 16.76. Found: C, 59.89; H, 6.56; N: 16.40.