Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[N:3]=1.[F:24][C:25]([F:31])([F:30])[CH2:26][N:27]=[C:28]=[S:29]>C(#N)C>[F:24][C:25]([F:31])([F:30])[CH2:26][NH:27][C:28](=[S:29])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1ccnc(SCCCCN2C(=O)c3ccccc3C2=O)n1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 48 h
Yield: 69.9 %

Procedure:
A mixture of 4-amino-2-(4-phthalimidobutylthio)pyrimidine (0.49 g.), acetonitrile (5 ml.) and 2,2,2-trifluoroethylisothiocyanate (0.28 g.) was stirred at 70° for 48 hours. A further 0.28 g. of 2,2,2-trifluoroethylisothiocyanate was added and the mixture stirred at 70° for 48 hours. The reaction mixture was cooled and filtered, the residue stirred with N aqueous acetic acid and the undissolved solid collected to give 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobutylthio)pyrimidine (0.49 g.), m.p. 201°-202° after recrystallisation from a mixture of ethanol and dimethylformamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[O:11][CH2:12][O:13][CH3:14].C(=O)(O)[O-].[Na+].[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1)#[N:21]>O1CCCC1.O>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([O:32][CH3:33])=[C:26]([S:28]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=2[O:11][CH2:12][O:13][CH3:14])(=[O:30])=[O:29])[CH:27]=1)#[N:21]
Reactant: COCOc1cc(O)ccc1CCN
Reactant: COc1ccc(C#N)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc(O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
4-(2-Aminoethyl)-3-methoxymethoxyphenol(12.3 g) and 7.9 g of sodium bicarbonate were suspended in a mixture of 133 mL of tetrahydrofuran and 14.4 mL of water. To the resulting suspension were added 18 mL portions of a solution of 14.50 g of 5-cyano-2-methoxybenzensulfonyl chloride in 180 mL of tetrahydrofuran every 10 minutes while the internal temperature was kept at 10-20° C. After being stirred at room temperature for 8 hours, the reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate), and recrystallized from ethyl acetate-diisopropyl ether to give 21.87 g of 5-cyano-N-[2-(4-hydroxy-2-methoxy methoxyphenyl)ethyl]-2-methoxybenzenesulfonamide as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][C@H:38]([CH3:42])[CH2:37]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:39]5[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][O:33][CH3:32])[CH2:37][C@H:38]5[CH3:42])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: COCCN1CCN[C@H](C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCCN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@H](C)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(2-methoxyethyl)-2-(R)-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-(2-Methoxy-ethyl)-3-(R)-methyl-piperazine following general procedure C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40](O)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][O:47][C@@H:48]1[CH2:52][CH2:51][NH:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40]([N:50]4[CH2:51][CH2:52][C@@H:48]([O:47][CH3:46])[CH2:49]4)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Reactant: CO[C@@H]1CCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)N3CC[C@@H](OC)C3)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with (R)-3-methoxy-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3078.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH2:31](O)C.C(NC(C)C)(C)C>[Pd].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH2:29][CH3:31])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCO
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: [Pd]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CCC(C(=O)OC(C)(C)C)N1CCC(NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reaction time: 18 h

Procedure:
A mixture of Intermediate 112 [Mixture 1] (0.051 g), 10% palladium on carbon (0.01 g) and ethanol (5 ml) was stirred under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give a yellow gum. The gum (0.034 g) in DCM (2 ml) was treated with 6-chloronaphthylsulphonyl chloride1 (0.04 g) and N,N-diisopropylamine (0.073 ml) and stirred at room temperature for 24 h. The mixture was washed with water and concentrated under reduced pressure to yield an oil which was partially purified using SPE (silica, eluting with cyclohexane:ethyl acetate 1:1) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:8]=2[CH:21]=1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36])[C:28](O)=O)#[N:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:23]([C:25]1[CH:26]=[C:27]([C:28]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9][C:8]=4[CH:21]=3)[N:22]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:36])[CH3:37])#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C(=N)NO)cc2C1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)no2)cc1C#N
Temperature: 120 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
A solution of 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 75) (0.84 g, 2.73 mmol), 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (0.617 g, 3.01 mmol), EDC (0.786 g, 4.10 mmol) and HOBT (0.502 g, 3.28 mmol) in DMF (10 ml) was stirred at RT overnight. Additional EDC (0.4 g) was added and the reaction stirred for 3 hours. Then additional 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (0.3 g) was added, the reaction heated at 120° C. for 1 hour and left standing overnight. The reaction mixture was partitioned between EtOAc/water, and the organic layer collected, dried (MgSO4) and evaporated. The resulting crude was purified by flash chromatography eluting with EtOAc/iso-hexane 20-30%. Analysis of the puried fractions by LCMS showed some 3-cyano-4-[(1-methylethyl)oxy]benzoic acid present so sodium bicarbonate and EtOAc was added. The EtOAc layer was separated, dried (MgSO4) and evaporated to give the title compound (410 mg) as a white solid. MS (ES): C26H28N4O5 requires 476; found 421 [M+H−56]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[OH-].[Na+]>C(O)C.C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCCc1cc(C(=O)OCC)c2cnn(C(C)C)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)O)c2cnn(C(C)C)c2n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of ethyl 1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (180 mg, 0.654 mmol) in ethanol (5 mL) and THF (1 mL) was added sodium hydroxide (1.090 mL, 3.27 mmol), and the mixture was stirred at 40° C. for 1 h. The volatiles were removed under reduced pressure. The aqueous phase was acidified to pH 3 with aq. 1N HCl. The solid precipitate formed was collected by filtration and dried under high vacuum to give 144 mg (89%) of product, which was used for next reaction without further purification. LCMS E-S (M+H)=248.1 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.12 (m, 3H), 1.50 (d, J=6.6 Hz, 6H), 1.78 (m, 2H), 2.80-3.11 (m, 2H), 5.09-5.38 (m, 1H), 7.47-7.72 (s, 1H), 8.18-8.46 (s, 1H), 13.82 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]([CH3:19])[CH2:13]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][C@@H:14]([CH3:19])[CH2:15][C@H:16]([CH3:18])[CH2:17]2)=[CH:6][CH:5]=1)([CH3:22])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(OCCCN2C[C@@H](C)C[C@H](C)C2)cc1
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](C)CN(CCCOc2ccc(C(C)(C)O)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of trans-1-[3-(4-acetylphenoxy)propyl]-3,5-dimethylpiperidine (289 mg) in tetrahydrofuran (1 mL) is stirred at room temperature under anhydrous atmosphere and a 2.61 M solution of methylmagnesium bromide in tetrahydrofuran (400 μL) is added dropwise. The mixture is stirred at room temperature for 3 h and quenched with a saturated aqueous solution of ammonium chloride. The solution is extracted with ethyl acetate and the combined extracts washed with water, dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with dichloro-methane/methanol 95/5 as eluent. Fractions containing the expected product are pooled and salted with 20 mg of oxalic acid to give 70 mg of trans-1-{3-[4-(1-hydroxy-1-methylethyl)-phenoxy]propyl}-3,5-dimethylpiperidine, oxalate as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.I[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Reactant: O=[N+]([O-])c1cccc(I)c1
Product: O=[N+]([O-])c1cccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)c1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (3.9 g, 10 mmol) was treated as described in general procedure B using 1-iodo-3-nitrobenzene to give 2-(4-bromo-benzyl)-1-(3-nitro-phenyl)-4-(2,4-dichloro-phenyl)-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]([NH:13]C(=O)CC1C=CC=CC=1[N+]([O-])=O)([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][C:2]([CH3:12])([NH2:13])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(CCCc1cccnc1)NC(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(N)CCCc1cccnc1
Yield: 77.8 %

Procedure:
A solution of 35.2 g of N-[1.1-dimethyl-4-(3-pyridyl) butyl]-2-nitrobenzeneacetamide in 250 mL of acetic acid was hydrogenated over 3.5 g of 10% Pd/C at atmospheric Pressure and ambient temperature. The reaction was exothermic and stopped abruptly after the uptake of the theoretical amount of hydrogen (7.5 L). The catalyst was removed by filtration and the filtrate was heated at reflux for 90 minutes. After the solution was cooled. 10 mL of conc. HCl was added and the solvent was removed under reduced pressure. The residue was taken up in IL of water and extracted with ethyl acetate (4×200 mL) to remove the by product, oxindole. The aqueous layer was basified with 10N NaOH and extracted with dichloromethane to give. after evaporation of the dried (K2CO3) extracts 15 g of product. The material was distilled on a Kugelrohr apparatus (95° C; 0.1 mm) to yield 14.3 g of alpha,alphadimethyl-3-pyridinebutanamine.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:11]12[CH3:12])[C@:24]1([CH3:25])[C@H:19]([CH:20]=[C:21]([P:29]([O:33][CH3:34])(=[O:32])[O:30][CH3:31])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)(C(C)(C)C)(C)C.CC(C)=[O:37].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH3:31][O:30][P:29]([C:21]1[CH2:22][CH2:23][C@@:24]2([CH3:25])[CH:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:26]2[CH2:27][CH2:28][C@@:11]2([CH3:12])[C@H:13]3[CH2:14][CH2:15][C@@H:10]2[C:9]([OH:37])=[O:8])[CH:20]=1)([O:33][CH3:34])=[O:32]
Reactant: COP(=O)(OC)C1=C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](CO[Si](C)(C)C(C)(C)C)CC[C@@H]34)[C@@]2(C)CC1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COP(=O)(OC)C1=CC2CC[C@H]3[C@@H]4CC[C@H](C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Yield: 99 %

Procedure:
Dimethyl 17β-(t-butyldimethylsilyloxymethyl)-5α-androst-3-ene-3-phosphonate (500 mg), was dissolved in 150 ml acetone. Jones reagent was added until a red color persisted. Isopropanol was then added to quench excess Jones reagent. The acetone was decanted off and the residual chromium salts were then dissolved in water and washed 3 times with dichloromethane. The organic layers were combined and passed through a plug of florosil and concentrated to give 360 mg (99%) of 3-dimethylphosphono-3-androstene-17β-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)=[O:3].C(O)C.[H-].[Na+].Cl.[C:24](=O)([O:28]CC)[O:25][CH2:26][CH3:27]>O>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:24]([O:25][CH2:26][CH3:27])=[O:28])[CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-benzyloxyacetophenone (90 g, 400 mmol) in diethyl carbonate (500 ml) was added ethanol (1.5 ml) and sodium hydride (60% in oil, 31.8 g, 800 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 4 hrs. To the reaction solution was added 6N hydrochloric acid to stop the reaction, and water (500 ml) was added. The mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-10:1) to give the objective substance (107 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:8][CH:9]=1
Reactant: COC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1csc(NC(=O)C(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h

Procedure:
(2-Amino-thiazol-4-yl)-acetic acid methyl ester (45 mg, 0.20 mmol) and diphenyl-acetic acid (37 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (29.4 mg, 0.0802 mmol, 40. %). ESI-MS m/z calc. 380.1. found 381.3 (M+1)+ Retention time 3.28 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH:10]([NH2:13])([CH3:12])[CH3:11]>CS(C)=O>[Cl:8][C:4]1[N+:3]([O-:9])=[C:2]([NH:13][CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)N
Reactant: [O-][n+]1c(Cl)cccc1Cl
Solvent: CS(C)=O
Product: CC(C)Nc1cccc(Cl)[n+]1[O-]
Temperature: 120 °C

Procedure:
To a solution consisting of 10 grams (0.06 mole) of 2,6-dichloropyridine-N-oxide in 50 milliliters of dimethylsulfoxide was slowly added 7.9 grams (0.134 mole) of isopropylamine. The temperature of the mixture was 90°C. at the start of the reaction and was allowed to increase to 120°C. After a total reaction time of ~50 minutes, 3/4 of the dimethylsulfoxide was removed by evaporation and the reaction mixture poured over ice. The solid precipitate which formed was removed by filtration and taken up in 500 milliliters of hot hexane. The 6-chloro-2-(isopropylamino)pyridine-N-oxide product melting at 150°-151°C. and was recovered by filtration in a yield of 5 grams. Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 51.47, 5.96, 19.01 and 15.01 percent, respectively, as compared with the theoretical contents of 51.46, 5.94, 18.99 and 14.99 percent, respectively, calculated for the above named compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[Br-].[C:17]([Zn+])([CH3:20])([CH3:19])[CH3:18].C1COCC1>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>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Zn+]
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccc(C(C)(C)C)nc2)cs1
Temperature: 150 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 50 mg (0.043 mmol, 0.05 eq) tetrakis(triphenylphosphine)palladium(0), and 2 mL of 0.5 M t-butylzinc bromide in THF (1 mmol, 1.1 eq) were combined. The reaction mixture was heated at 150° C. in the microwave for 5 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 5% to 50% EtOAc/Hexanes) gave 2-tert-butyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001109555). LC-MS calculated for C15H16N2S 256, observed m/e 257.0 (M+H)+. 1H-NMR (500MHz, CDCl3) δ 8.74 (s, 1H), 7.76 (d, 1H), 7.45 (s, 1H), 7.12 (d, 1H), 2.77 (s, 3H), 2.12 (m, 1H), 0.97 (d, 9H).
Reaction SMILES: ClC[C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8](O)=[O:9])=O.COC(=O)C1C(=CC=CC=1)[NH2:20]>>[N:5]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:20][CH:3]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Product: O=c1[nH]cnc2ccccc12

Procedure:
2-Chloromethyl-3-82-methoxycarbonyl-phenyl)-4H-quinazolin-4-one (melting point: 197°-199° C., recrystallised from toluene) was prepared from N-chloroacetyl-anthranilic acid and anthranilic acid methyl ester analogously to the method in J. pr. Chem. (4) 14 (1961), 84.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[C:11]([C:10]1[CH:9]=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:3][CH2:4]2)[CH:15]=[CH:14][CH:13]=1)#[N:12]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: N#Cc1cccc(C2=CCC(=O)CC2)c1
Product: N#Cc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from hydrogenation of 3-(4-oxo-cyclohex-1-enyl)-benzonitrile (as prepared in the previous step) followed by reductive amination of the corresponding ketone with N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedures described in Step C of Example 5 and Step C of Example 4.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:23]([O:25]C(C)(C)C)=[O:24])([C:16]([O:18]C(C)(C)C)=[O:17])[CH2:10][CH:9]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[CH2:14]([O:13][C:11]([CH:9]1[CH2:10][C:8]1([C:23]([OH:25])=[O:24])[C:16]([OH:18])=[O:17])=[O:12])[CH3:15]
Reactant: CCOC(=O)C1CC1(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC1(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 123.7 %

Procedure:
TFA (4.5 g, 39.7 mmol) was added into a solution of 1,1-di-tert-butyl 2-ethyl cyclopropane-1,1,2-tricarboxylate (4.9 g, 13.2 mmol) in dichloromethane (20 mL) and the mixture was stirred at room temperature for 48 h. The solvent was evaporated in vacuo and the excess TFA was lyophilized to afford 2-(ethoxycarbonyl)cyclopropane-1,1-dicarboxylic acid (3.3 g, 100%). 1H NMR (300 MHz, CD3OD): δ 1.23-1.29 (t, J=6.9 Hz, 3H), 1.60-1.64 (m, 1H), 1.85-1.88 (m, 1H), 2.48-2.53 (m, 1H), 4.10-4.18 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[NH4+].[Cl-]>CO.[Zn]>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)[C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1c(-c2cccc([N+](=O)[O-])c2)nsc1N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: NC(=O)c1c(-c2cccc(N)c2)nsc1N
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A mixture of 5-amino-3-(3-nitrophenyl)isothiazole-4-carboxamide (150 mg, 0.57 mmol), 0.5 mL saturated aqueous NH4Cl, and catalytic Zn powder in 6 mL MeOH was rapidly stirred at rt. After 1.5 hours additional saturated aqueous NH4Cl and catalytic Zn powder was added several times to push the reaction to completion. At 20 hours the reaction was heated at 55° C. for 6 hours, then stirred overnight at rt. The reaction was filtered using Celite and the solids rinsed with MeOH, the filtrate evaporated and treated to an aqueous workup using EtOAc and aqueous Na2CO3 to give a pale yellow solid. The solid was triturated with EtOAc/hexane to give 94 mg of faint yellow solid. Then the filtrate lot and the 94 mg of solid were separately chromatographed eluting with hexane/acetone and combined to give the title compound as an off-white solid (96 mg, 72%).