Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH2:28][C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32](O)=[O:33])[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1.[CH3:38][O:39][CH:40]([O:43][CH3:44])[CH2:41][NH2:42].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH2:28][C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:42][CH2:41][CH:40]([O:43][CH3:44])[O:39][CH3:38])=[O:33])[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=C(O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Reactant: COC(CN)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(CNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
906 mg (4.73 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) are added to a solution of 1.24 g (3.64 mmol) of 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]benzoic acid (prepared in accordance with WO 2008/017361), 382 mg (3.64 mmol) of aminoacetaldehyde dimethyl acetal and 557 mg (3.64 mmol) of 1-hydroxybenzotriazole hydrate (HOBt) in 14 ml of DMF, and the mixture is stirred overnight at room temperature. Water is added to the reaction mixture. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-N-(2,2-dimethoxyethyl)benzamide as colourless crystals; ESI 430.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=[N:55][C:53]=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[CH:14]=[CH:13][C:9]=1[C:10]([NH:55][CH2:53][C:38]1[CH:39]=[N:40][CH:35]=[CH:36][CH:37]=1)=[O:11]
Reactant: O=C(O)c1ccc(-c2cn[nH]c2)nc1NCCc1cccc(F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: On1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc(-c2cn[nH]c2)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a mixture of 2-(3-fluorophenethylamino)-6-(1H-pyrazol-4-yl)nicotinic acid (prepared according to example 1, method A) (1.0 g, 3.07 mmol) in DMF (10 mL) was added HBTU (1.75 g, 4.6 mmol), HOBt (0.62 g, 4.6 mmol), then amine 7 (0.66 g, 6.13 mmol). The reaction mixture was stirred at room temperature for 2 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 2-(3-fluorophenethylamino)-6-(1H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)nicotinamide as a pale yellow solid (0.79 g, 62%). LRMS (M+H+) m/z 417.1.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:30][CH:31]([CH3:33])[CH3:32])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([OH:29])=O)[CH2:8]2)=[CH:3][CH:2]=1.[NH2:40][C@:41]1([C:46]([NH:48][S:49]([CH:52]2[CH2:54][CH2:53]2)(=[O:51])=[O:50])=[O:47])[CH2:43][C@H:42]1[CH:44]=[CH2:45].CC1C=CC(S(O)(=O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:30][CH:31]([CH3:32])[CH3:33])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:14]([CH3:16])([CH3:17])[CH3:15])[C@H:9]([C:27](=[O:29])[NH:40][C@:41]3([C:46](=[O:47])[NH:48][S:49]([CH:52]4[CH2:54][CH2:53]4)(=[O:51])=[O:50])[CH2:43][C@H:42]3[CH:44]=[CH2:45])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)S[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To an iced slurry of (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylic acid (28 mg, 0.050 mmol), (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide, pTSA, 0.68H2O (23.03 mg, 0.056 mmol), and HATU (28.5 mg, 0.075 mmol) in DCM (1 mL) was added N,N-Diisopropylethylamine (0.035 mL, 0.202 mmol). The formed light brown solution was stirred at room temperature overnight. Diluted with EtOAc, washed it with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated. The formed residue was purified by prep-HPLC to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(biphenyl-4-yl)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(isopropylthio)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (23 mg, 59% yield) as a white solid. 1H NMR (500 MHz, MeOD) ppm 1.03-1.07 (m, 3H), 1.09-1.12 (m, 11H), 1.21-1.28 (m, 4H), 1.40-1.51 (m, 2H), 1.52 (s, 9H), 1.87 (dd, J=7.93, 5.49 Hz, 1H), 2.20 (q, J=8.85 Hz, 1H), 2.30 (t, J=11.60 Hz, 1H), 2.54-2.62 (m, 1H), 2.81 (dd, J=12.05, 6.26 Hz, 1H), 2.90-2.98 (m, 1H), 3.87 (dd, J=10.99, 6.41 Hz, 1H), 3.97 (d, J=0.99 Hz, 1H), 4.51 (d, J=9.77 Hz, 1H), 5.08-5.19 (m, 2H), 5.29 (d, J=17.09 Hz, 1H), 5.69-5.81 (m, 1H), 7.37 (t, J=7.32 Hz, 1H), 7.46 (t, J=7.78 Hz, 2H), 7.60 (dd, J=10.68, 7.93 Hz, 4H), 7.71 (d, J=8.55 Hz, 2H). LC-MS (retention time: 3.42 min, method B), MS m/z 767 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:34])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16]([N:27]4[CH2:31][CH2:30][CH2:29][CH:28]4[CH3:32])[N:15]=3)[C@H:10]([CH3:33])[CH2:9]2)=[N:6][CH:7]=1.[CH3:35][N:36](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:17]=[C:16]([N:27]3[CH2:31][CH2:30][CH2:29][CH:28]3[CH3:32])[N:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[C:4]([CH3:34])=[CH:3][C:2]([C:35]#[N:36])=[CH:7][N:6]=4)[CH2:9][C@H:10]3[CH3:33])[CH:19]=2)=[CH:25][CH:24]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCCC3C)n2)[C@H](C)C1
Temperature: 25 °C

Procedure:
To a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (700 mg, 1.33 mmol) and Zn(CN)2 (94 mg, 0.799 mmol) in DMF, add Pd(PPh3)4 (77 mg, 0.067 mmol). Purge the reaction mixture for 10 min with dry N2. Heat the stirring reaction mixture overnight at 80° C., cool to room temperature and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:1) to afford the title compound as a white solid.
Reaction SMILES: BrC[C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[NH:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([O:22][CH3:23])=[O:21].[K].O.[CH3:33]N(C=O)C>>[C:27]([O:26][C:24]([N:19]([CH2:33][C:5]1[C:4]([N+:16]([O-:18])=[O:17])=[CH:3][CH:15]=[CH:14][C:6]=1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C:20]([O:22][CH3:23])=[O:21])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CN(C)C=O
Reactant: COC(=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: [K]
Solvent: O
Product: COC(=O)N(Cc1c(C(=O)OC(C)(C)C)cccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of t-butyl 4-bromomethyl-3-nitrobenzoate (2.27 g, 7.2 mmol) (Int. J. Peptide Res., 36, 31 (1990)) in DMF (25 mL) was added a suspension of potassium t-butyl methyl iminodicarboxylate (J.C.S. Perkin I, 1088, (1977)) (1.56 g, 7.3 mmol) in DMF (20 mL). The dark brown solution was stirred 1 h and poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, dried (sodium sulfate) and concentrated to give a pale orange oil which was purified by flash chromatography (silica gel, 20% ethyl acetate/hexane) to give the title compound (2.15 g, 73%). 1H NMR (400 MHz, CDCl3) δ8.65 (s, 1H), 8.2 (d, 1H), 7.45 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 1.6 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: C([N:3](CC)CC)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:35])=[C:13]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[C:31]([C:32]([OH:34])=O)=[CH:30][N:29]=[CH:28][CH:27]=3)[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[CH:14]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N[CH:70]([CH3:78])[CH2:71][N:72]1[CH2:76][CH2:75][CH2:74][C:73]1=[O:77]>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([F:35])=[C:13]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[C:31]([C:32]([NH:3][CH2:78][CH2:70][CH2:71][N:72]4[CH2:76][CH2:75][CH2:74][C:73]4=[O:77])=[O:34])=[CH:30][N:29]=[CH:28][CH:27]=3)[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[N:16]=2)[CH:14]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: CC(N)CN1CCCC1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: O=C(NCCCN1CCCC1=O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
Triethylamine (140 μL, 1.00 mmol) was slowly added to a solution of 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic acid 16 (150 mg, 0.340 mmol), PyBOP (0.350 mg, 0.68 mmol), and 1-(β-aminopropyl)pyrrolidinone (97 mg, 0.68 mmol) in CH2Cl2 (10 mL). After 15 min at room temperature, the reaction mixture was evaporated and the residue purified by column chromatography (AcOEt/CH2Cl2, 2:1+1% triethylamine to AcOEt/CH2Cl2/MeOH, 7:2:1+1% triethylamine). The yellow powder was recrystallized from EtOH to give 58 mg of the title product 21 as yellow prisms (LCMS analysis).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:27][CH3:28])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccc2nonc12
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2cccc3nonc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,1,3-benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 39.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[C:14]([CH3:15])=[CH:13][S:12][CH:11]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:34])N(OC)C)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([C:11]2[S:12][CH:13]=[C:14]([CH3:15])[C:10]=2[Br:9])=[O:34])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cscc1Br
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1csc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Under inert conditions, add a 2.0 M solution (in tetrahydrofuran/n-heptane) of lithium diisopropylamide (29.65 mmol, 14.83 mL, 1.05 equivalents) to a cold (−78° C.) solution of 3-bromo-4-methylthiophene (28.24 mmol, 5.00 g, 1.00 equivalents) in dry tetrahydrofuran (27.33 mL). Stir at −78° C. for 1 hour and add a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (28.24 mmol, 7.69 g, 1.00 equivalents), dropwise. Continue stirring at −78 ° C. for 3 hours. Quench the reaction mixture with saturated ammonium chloride (aqueous, 55 mL) and allow to warm to room temperature. Extract the reaction mixture with a mixture of ethyl acetate : diethyl ether (1:1, 3×40 mL). Combine the extracts and dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography using a mixture of n-heptane:ethyl acetate (4:1) to yield a yellow, crystalline solid (9.84 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=O)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH2:40])[CH:36]=[N:37][CH:38]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH:40][C:25]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]=2[CH:22]([CH3:24])[CH3:23])=[O:27])[CH:36]=[N:37][CH:38]=1
Reactant: NCc1cncc(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3cncc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 150 mg, 0.41 mmol) in CH2Cl2 (25 ml) was added EDC (236 mg, 0.82 mmol) and DMAP (75 mg, 0.60 mmol), followed by (5-fluoropyridin-3-yl)methanamine (94 mg, 0.82 mmol). The crude material was purified by chromatography on silica gel (0→80% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C)[C:5]2[O:10][CH2:9][CH2:8][C:7](C#N)(O[Si](C)(C)C)[C:6]=2[CH:18]=1.[C:20]([OH:23])(=[O:22])[CH3:21]>>[ClH:1].[Cl:1][C:2]1[CH:18]=[C:6]([CH3:7])[C:5]2[O:10][CH2:9][CH2:8][CH:21]([C:20]([OH:23])=[O:22])[C:4]=2[CH:3]=1
Reactant: Cc1cc(Cl)cc2c1OCCC2(C#N)O[Si](C)(C)C
Reactant: CC(=O)O
Product: Cc1cc(Cl)cc2c1OCCC2C(=O)O
Product: Cl

Procedure:
Following the procedure of Example 2, 6-chloro-8-methyl-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzopyran (3.1 g.), and stannous chloride dihydrate (12.0 g.) were reacted in glacial acetic acid (25 ml.) and concentrated hydrochloric acid (25 ml.) to form 6-chloro-8-methyl-3,4-dihydro-2H-1-benzopyran-4-carboxylic acid. Recrystallization from hexane yielded 1.67 g. of product, m.p. 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C-:14]#[N:15].[Li+].O1CCOCCOCCOCC1>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>[Cl:1][C:2]1[N:12]=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CN(C)C(=O)c1cc(I)cnc1Cl
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCO1
Agent: [Li+]
Solvent: c1ccccc1
Product: CN(C)C(=O)c1cc(C#N)cnc1Cl
Temperature: 40 °C
Yield: 54.4 %

Procedure:
A mixture of 2-chloro-5-iodo-N,N-dimethylnicotinamide (1.54 g, 5 mmol), prepared as in Example 14, and lithium cyanide (0.5M in DMF, 20 mL, 10 mmol) was distilled at reduced pressure. The residue was suspended in 1,4,7,10-tetraoxacyclo-dodecane (0.2 mL, 1.25 mmol) in 50 mL of benzene and the mixture was distilled under nitrogen until a forefraction of approximately 5 mL had collected. The suspension was allowed to cool and then tetrakis(triphenylphosphine)palladium(0) (2.44 g, 2.1 mmol) was added. The mixture was stirred at 40° C. under nitrogen for 1 week, allowed to cool to room temperature and partitioned between aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with diethyl ether and the extract was washed with brine, dried (Na2 SO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (5:1) to give 2-chloro-5-cyano-N,N-dimethylnicotinamide (0.57 g, 2.72 mmol), m.p. 148°-153° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27][N:28]1[C:34]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=2[CH:32]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[NH:31][CH2:30][C:29]1=[O:46]>C(N(CC)CC)C.O1CCCC1>[CH3:27][N:28]1[C:34]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=2[CH:32]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:31]([C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:30][C:29]1=[O:46]
Reactant: CN1C(=O)CNC(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN1C(=O)CN(C(=O)CNC(=O)OCc2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Reaction time: 0.33 h
Yield: 90 %

Procedure:
2.8 g. (13.4 mmoles) of benzyloxycarbonyl-glycine are suspended in 27 ml. of dry ether, and 3 g. (15 mmoles) of phosphorous pentachloride are added in portions to the suspension at 0° C. The mixture is stirred for 20 minutes, and thereafter a solution of 2.86 g. (10 mmoles) of 1-methyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 15 ml. of dry tetrahydrofuran containing 9 ml. of triethylamine is added dropwise to the obtained solution. The reaction mixture is stirred in an ice bath for 6 hours, and evaporated to dryness under reduced pressure. The oily residue is dissolved in 100 ml. of chloroform, the chloroform solution is washed with 3×50 ml. of water, 1×50 ml. of sodium bicarbonate solution and with water again, dried, and evaporated to dryness under reduced pressure. The oily residue is covered with ether, upon which is solidifies. 4.28 g. (90 %) of 1-methyl-4-(N-benzyloxycarbonyl-aminoacetyl)-5-phenyl- 7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 158°-160° C. (after recrystallization from ethanol), Rf2 = 0.60. Analysis: Calculated for C26H24O4N3Cl (M = 477.93): C: 65.2 % H: 5.1 % N: 8.8 % Found: C: 65.5 % H: 4.9 % N: 8.9 %
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[CH2:10][C:11](Cl)=[O:12].[CH2:14]([N:18]=[C:19]=[S:20])[CH2:15][CH2:16][CH3:17]>>[CH2:14](/[N:18]=[C:19]1\[S:20][CH2:10][C:11](=[O:12])[N:8]\1[C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN=C=S
Reactant: O=C(Cl)CCl
Reactant: Cc1ccccc1N
Product: CCCC/N=C1\SCC(=O)N1c1ccccc1C

Procedure:
2-[(Z)-n-butylimino]-3-(2-methylphenyl)-thiazolidin-4-one is prepared following Method B and starting from o-tolylamine, chloroacetyl chloride and n-butylisothiocyanate. LC-MS: tR=0.77 min, [M+1]+=263, 1H NMR (CDCl3): δ 7.35-7.28 (m, 3H), 7.14-7.10 (m, 1H), 4.01 (s, 2H), 3.38-3.22 (, 2H), 2.18 (s, 3H), 1.59-1.47 (m, 2H), 1.38-1.25 (m, 2H), 0.90 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[Cl:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[Cl:14].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]3[CH2:36][C@H:35]4[C@:37]5([CH2:41][N:40]([CH2:42][C:43]([F:46])([F:45])[F:44])[S:39](=[O:48])(=[O:47])[NH:38]5)[C@H:32]([CH2:33][CH2:34]4)[CH2:31][C:30]=3[CH:49]=2)O1>>[Cl:7][C:8]1[CH:9]=[C:10]([N:5]2[CH:6]=[C:2]([C:26]3[CH:27]=[CH:28][C:29]4[CH2:36][C@H:35]5[C@:37]6([CH2:41][N:40]([CH2:42][C:43]([F:46])([F:45])[F:44])[S:39](=[O:47])(=[O:48])[NH:38]6)[C@H:32]([CH2:33][CH2:34]5)[CH2:31][C:30]=4[CH:49]=3)[N:3]=[CH:4]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Brc1c[nH]cn1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(Cl)c(Cl)c4)cn3)cc2C1

Procedure:
Prepared from 4-bromo-1H-imidazole, 3,4-dichlorophenylboronic acid and homochiral boronate from Example 24 Step 1 following the procedures in Example 76 Steps 1 and 2. δ (1H, 400 MHz, CDCl3) 1.24-1.28 (2H, m), 1.70-1.74 (2H, m), 2.42-2.49 (2H, m), 2.69-2.81 (2H, m), 3.20-3.26 (2H, m), 3.44 (2H, s), 3.68 (2H, q, J=8.7 Hz), 4.73 (1H, s), 7.13 (1H, d, J=7.8 Hz), 7.31 (1H, dd, J=8.6, 2.6 Hz), 7.50-7.61 (5H, m), 7.87 (1H, d, J=1 Hz). MS (ES+) 571, 573, 575 ([MH]+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[CH2:10][CH2:9][CH:8]([OH:11])[C:7]2[CH:12]=[CH:13][O:14][C:6]=2[CH2:5]1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([Cl:27])[CH:21]=1)(=[O:19])[NH2:18]>>[ClH:27].[C:17]([C:20]1[CH:25]=[CH:24][C:23]([O:11][CH:8]2[CH2:9][CH2:10][N:4]([CH2:3][C:2]([F:1])([F:15])[F:16])[CH2:5][C:6]3[O:14][CH:13]=[CH:12][C:7]2=3)=[C:22]([Cl:27])[CH:21]=1)(=[O:19])[NH2:18]
Reactant: OC1CCN(CC(F)(F)F)Cc2occc21
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Product: Cl
Product: NC(=O)c1ccc(OC2CCN(CC(F)(F)F)Cc3occc32)c(Cl)c1

Procedure:
The same method as in Example 3 was conducted using 7-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 38) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.[C:12]([C@H:16]1[CH2:20]OS(=O)(=O)[O:17]1)([CH3:15])([CH3:14])[CH3:13].C(Cl)(=O)C.C(=O)(O)[O-].[Na+]>C(#N)C.CO>[CH3:13][C:12]([CH3:15])([CH3:14])[C@H:16]([OH:17])[CH2:20][N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1
Reactant: CC(C)(C)[C@H]1COS(=O)(=O)O1
Reactant: c1cncc(-c2cc[nH]n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)Cl
Solvent: CC#N
Product: CC(C)(C)[C@H](O)Cn1ccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a solution of 0.38 g (2.62 mmol) of 3-(1H-pyrazol-3-yl)pyridine and 0.47 g (2.62 mmol) of (4S)-4-tert-butyl-1,3,2-dioxathiolane 2,2-dioxide in 15 mL of acetonitrile was added 1.3 g of a potassium fluoride/alumina mixture [prepared by mixing 10 g of potassium fluoride, 200 mL of water, and 15 g of activated neutral alumina (Brockmann I, 150 mesh) and concentrating at 55° C.]. The mixture was stirred at ambient temperature for 4 h. Then, a solution of 2 mL of acetyl chloride in 10 mL of methanol was added to the reaction mixture. After 18 h, saturated aqueous sodium bicarbonate was added, the mixture was filtered, and the filter cake was rinsed with methanol. The filtrate was concentrated, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated to provide 0.6 g (94%) of (2S)-3,3-dimethyl-1-[3-(3-pyridinyl)-1H-pyrazol-1-yl]-2-butanol as a yellow solid. 1H-NMR (DMSO-d6): δ 8.97 (s, 1H), 8.45 (d, J=4 Hz, 1H), 8.1 (t, J=8 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.38 (dd, J=8 Hz, J=5 Hz, 1H), 4.86 (d, J=6 Hz, 1H), 4.27 (dd, J=13 Hz, J=2 Hz, 1H), 3.90 (dd, J=14 Hz, J=10 Hz, 1H), 3.5–3.4 (m, 1H), 0.90(s, 9H).