Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH2:39]>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])=[O:22])(=[O:15])=[O:16])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CN(C)CCCN
Product: CN(C)CCCNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.033 cm3 of N,N-dimethyl-1,3-propanediamine. 52 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamide are thus obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.65 (mt, 2H), 2.18 (s, 6H), from 2.20 to 2.35 (mt, 2H), 2.98 (s, 3H), from 3.25 to 3.45 (mt, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.57 (t, J=5.5 Hz, 1H)].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[C:39](O)=[O:40]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:39]([C:30]2[CH:31]=[CH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]=2[OH:28])=[O:40])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1C[C@@H](c2ncc(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: O=C(N[C@H]1C[C@@H](c2ncc(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C32H28N3O5 [(M+H)+] 534, obsd. 534.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].C=O.[CH:30](O)=O>O1CCOCC1>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]3[CH2:21][CH2:20][N:19]([CH3:30])[CH2:18]3)(=[O:15])=[O:16])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: O=CO
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@@H]3CCNC3)ccc21
Agent: C=O
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@@H]3CCN(C)C3)ccc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of (R)—N,N-dimethyl-2-(2-neopentyl-5-(pyrrolidin-3-ylsulfonyl)-1H-benzo[d]imidazol-1-yl)ethanamine (STEP C, 453 mg, 1.15 mmol) in 1,4-dioxane (5 mL) was added 37% formalin (343 microL, 4.27 mmol) and formic acid (221 microL, 5.77 mmol) at 0° C. The mixture was stirred at 45° C. for 1 h. The mixture was concentrated in vacuo. The residue was diluted with sodium bicarbonate aqueous solution and extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with brine and dried over sodium sulfate. The resulting solution was concentrated and residue was purified by amine gel column chromatography (dichloromethane-ethyl acetate, gradient) to give the title compound (419 mg, 89%) as a clear grease.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccccc4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and benzoyl chloride (0.25 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.43 g, 64% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.17 min (99.25%); mp: 266-268° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H), 2.27-2.47 (m, 1H), 2.53-2.68 (m, 1H), 2.79-3.05 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.4 Hz, 1H), 4.60 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.0, 13.1 Hz, 1H), 7.42-7.62 (m, 5H), 7.70 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.0 Hz, 2H), 9.16 (t, J=5.9 Hz, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.7, 47.1, 51.6, 122.1, 122.9, 127.1, 127.2, 128.3, 130.3, 131.3, 134.2, 142.4, 144.0, 166.3, 167.9, 171.0, 172.8; LCMS: MH=378; Anal Calcd for C21H19N3O4: C, 66.83; H, 5.07; N, 11.13. Found: C, 66.75; H, 5.08; N, 11.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O.C[CH2:18][N:19]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN>CN(C)C=O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]([NH:19][CH3:18])=[O:16])[CH:5]=1)([O-:11])=[O:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc([N+](=O)[O-])cc1/C=C/C(=O)O
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)/C=C/c1cc([N+](=O)[O-])ccc1OC
Reaction time: 18 h
Yield: 70.9 %

Procedure:
(E)-3-(2-Methoxy-5-nitro-phenyl)-acrylic acid (Egypt. J. Pharm. Sci., (1996), 37, 71-84), (1.0 g) in dimethylformamide (5 ml) was treated with EDC.HCl (0.86 g), N-hydroxybenzotriazole (0.1 g) and methylamine (2M in tetrahydrofuran 3 ml) and stirred for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane, washed with 2N HCl, sodium hydrogen carbonate and brine. After drying (MgSO4), solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 5% methanol:dichloromethane) to give the title compound (0.75 g). 1H NMR δ: 2.71 (3H, d, J=4.7Hz), 4.01 (3H, s), 6.71 (1H, d, J=15.9 Hz), 7.30 (1H, d, J=9.2 Hz), 7.62 (1H, d, J=15.9 Hz), 8.09 (1H, m), 8.25 (1H, dd, J=2.8, 9.2 Hz), 8.36 (1H, d, J=2.8 Hz).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:20])([F:19])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3].[CH3:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH:33]=1)[C:30](O)=[O:31])(=[O:24])=[O:23]>>[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:19])([F:20])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][N:13]([C:30](=[O:31])[C:29]3[CH:33]=[C:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH:26]=[CH:27][C:28]=3[O:34][C@@H:35]([CH3:40])[C:36]([F:39])([F:37])[F:38])[CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1O[C@@H](C)C(F)(F)F)C2

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine-3-carboxylic acid ethyl ester hydrochloride (CA [741736-90-3]; WO2004069162) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.2). MS (m/e): 569.0 (M+H+).
Reaction SMILES: [O:1]=[C:2]([CH3:5])[CH:3]=[CH2:4].[CH3:6][NH:7][CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[CH3:6][N:7]([CH2:8][CH2:9][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:4][CH2:3][C:2](=[O:1])[CH3:5]
Reactant: C=CC(C)=O
Reactant: CNCCC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC(=O)CCN(C)CCC(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of 3.72 ml of 3-oxo-but-1-ene was added dropwise, over a period of 20 minutes and such that the temperature did not exceed 2°-3° C., to a cooled solution of 7.87 g of N-methyl-3,3-diphenylpropylamine in 7 ml of diethyl ether. The solution thus obtained was evaporated in vacuo at room temperature to give 10.3 g of N-methyl-N-(3,3-diphenylpropyl)-4-aminobutan-2-one (100%) as free base, shown to be practically pure by TLC (chloroform:methanol 9:1 by volume) which could be used as such for further reactions. This compound could be transformed into the corresponding hydrochloride (m.p. 133°-135° C.) by treating the free base with hydrogen chloride in diethyl ether, and crystallizing the product thus obtained first from acetone:ethyl acetate:isopropanol then from acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:9]2[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C1CN([P+](O[N:34]2N=[N:41][C:36]3C=CC=C[C:35]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:9]2[C:10]([NH:41][CH2:36][C:35]#[N:34])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C[C@@H](C(=O)O)N(c2cccc(Br)c2)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Product: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cccc(Br)c2)C1
Reaction time: 8 h

Procedure:
To (4S)-1-(3-bromophenyl)-4-methyl-L-proline (1.35 g, 4.75 mmol), PyBOP (2.72 g, 5.23 mmol), aminoacetonitrile hydrochloride (968 mg, 10.46 mmol) in dry DMW (30 mL) under dry nitrogen was added triethylamine (2.35 mL, 16.63 mmol) dropwise and the reaction was stirred overnight. Aqueous sat. NaHCO3 was added and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 35/75, then 4/6) to afford (4S)-1-(3-bromophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:38])[CH2:34][CH2:35][O:36][CH3:37]>>[CH3:37][O:36][CH2:35][CH2:34][C:33]1[N:38]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1
Reactant: COCCC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 36 mg (0.306 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 14 mg (18% of theory)
Reaction SMILES: C(O)(C)(C)C.Cl[C:7]1[CH:8]=[C:9]([N:14]2[C:19]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]=3[O:17][C:16]([CH3:30])([CH3:29])[C:15]2=[O:31])[CH:10]=[CH:11][C:12]=1[F:13].C(=O)([O-])[O-].[K+].[K+].[C:38](=[O:45])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[NH2:39]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(B(O)O)C=CC=CC=1>[CH3:29][C:16]1([CH3:30])[C:15](=[O:31])[N:14]([C:9]2[CH:10]=[CH:11][C:12]([F:13])=[C:7]([NH:39][C:38](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:8]=2)[C:19]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:18]=2[O:17]1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)c(Cl)c2)C1=O
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1cc(N2C(=O)C(C)(C)Oc3cc(NS(C)(=O)=O)ccc32)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 115.1 %

Procedure:
A mixture of palladium acetate (1.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (7.2 mg), phenylboronic acid (0.9 mg) and tert-butanol (2 mL) was stirred at room temperature for 20 minutes under argon atmosphere. To the reaction mixture were added N-[4-(3-chloro-4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 13, 60 mg), potassium carbonate (62 mg), tert-butyl carbamate (35 mg) and tert-butanol (5 mL), and the mixture was refluxed for 3 hours. To the reaction mixture were further added palladium acetate (1.3 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (7.2 mg), potassium carbonate (62 mg) and tert-butyl carbamate (35 mg), and the mixture was further refluxed for 20 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate =4/1→3/7) to give tert-butyl (5-{2,2-dimethyl-7-[(methylsulfonyl)amino]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}-2-fluorophenyl)-carbamate (83 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:14].[C:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])[CH3:16].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1.O>[C:15]([NH:18]/[C:19](=[CH:6]/[C:5]1[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:2]([NH2:1])=[C:3]([Cl:14])[CH:4]=1)/[C:20]([OH:22])=[O:21])(=[O:17])[CH3:16]
Reactant: CC(=O)NCC(=O)O
Reactant: Nc1c(Cl)cc(C=O)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N/C(=C/c1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Temperature: 128 °C
Reaction time: 2 h

Procedure:
A mixture of 50.0 g (224 mmol) 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde, 39.3 g (335 mmol) N-acetylglycine, 27.5 g (335 mmol) sodium acetate and 200 ml acetic anhydride was stirred for 2 hours in an oil bath at an oil bath temperature of 128° C. After cooling to an oil bath temperature of 90° C. 100 ml of water were added dropwise and the resulting suspension was added to a mixture of 1000 ml of water and 500 ml of toluene. The precipitate formed was suction filtered, washed with 300 ml of toluene and 500 ml of water and dried overnight at 60° C. in the circulating air dryer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COC(=O)c1cc(F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(F)ccc1-c1ncccn1
Temperature: 74 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a 250 mL round-bottomed flask, was added 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (5.9 g, 21.06 mmol) in 2-methyl-THF (50 mL). To the resulting solution was added 2-chloropyrimidine (2.9 g, 25.28 mmol), sodium carbonate (6.7 g, 63.19 mmol), and water (17 mL). The mixture was degassed for 30 minutes. PdCl2(dppf)-dcm adduct (0.688 g, 0.843 mmol) was added and the reaction mixture was degassed once more for 30 minutes. The reaction mixture was warmed to 74° C. and stirred overnight. To the resulting solution was added diethyl ether (100 mL) and water (100 mL). The layers were thoroughly mixed separated. The aqueous layer was extracted with additional diethyl ether (100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a brown crude material (5.85 g, 49% desired, 2.87 actual product). The crude product was further purified through recrystallization in 10% EA/hexanes. The mixture was warmed to 70° C. and cooled slowly to room temperature. After filtration, the desired product was obtained as a brown solid (1.72 g actual product, 35% yield overall after recrystallization). 1H NMR (400 MHz, CDCl3): 8.78 (d, J=4.9 Hz, 2H), 8.09 (dd, J=8.7, 5.5 Hz, 1H), 7.39 (dd, J=8.6, 2.7 Hz, 1H), 7.30-7.20 (m, 2H), 3.77 (s, 3H).
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=1.[I:29]I>C1COCC1>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[C:17]([I:29])[CH:16]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
To a solution of TMEDA (25.4 g, 219.3 mmol) in dry THF (300 mL) was added dropwise n-BuLi (87.7 mL, 219.3 mmol) at −78° C., the mixture was stirred for 0.5 h at this temperature. A solution of tert-butyl 6-chloropyridin-3-yl-carbamate (20 g, 87.7 mmol) in THF (170 mL) was added dropwise to the reaction mixture at −78° C. and the resulting mixture was continued to stir for 1 h at −78° C. Then a solution of I2 (26.7 g, 105.3 mmol) in dry THF (170 mL) was added dropwise at −78° C. After 1 h, the reaction was quenched with sat. aqueous NH4Cl (300 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10/1) to give tert-butyl 6-chloro-4-iodopyridin-3-ylcarbamate (10.0 g, 33%). 1H-NMR (CDCl3, 400 MHz) δ 8.95 (s, 1H), 7.73 (s, 1H), 6.64 (br s, 1H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][CH:5]=2.Cl[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][N:14]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nsc2ccccc12
Reactant: Cc1cc2c(C)cccc2[nH]1
Product: Cc1[nH]c2cccc(C)c2c1-c1nsc2ccccc12

Procedure:
The sub-title compound was prepared by the method of Example 16 step a) from 2,4 dimethyl indole and 3-chlorobenzisothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([F:9])=[CH:4][N:3]=1.C([Li])CCC.CON(C)[C:18](=[O:33])[CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:18](=[O:33])[CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)cc1I
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CC(c1ccccc1)c1ccccc1)c1cc(Cl)ncc1F
Reaction time: 1 h

Procedure:
At −70° C. to a solution of 2-chloro-5-fluoro-4-iodopyridine (873 mg) in THF (20 mL) was added n-butyllithium (2.2 mL, 1.6M in hexane) over a period of 15 min slowly. To that solution N-methoxy-N-methyl-3,3-diphenyl-propionamide (200 mg) in THF (8 mL) was added and stirring was continued at that temperature for 1 h. A saturated solution of NH4Cl was added, the mixture was diluted with EtOAc, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (CH2Cl2/n-heptane 1:2) to yield the title compound as a white solid, MS (ESI+): m/z=340.09 ([M+H]+, 1Cl).
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24][C:25]([CH3:31])([CH3:30])[O:26][C:27](=[O:29])[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])CC[CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=CC(C(C)C#N)=C(F)C=1.BrC1C=CC(C2(C#N)CCC2)=C(F)C=1>>[CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24][C:25]([CH3:31])([CH3:30])[O:26][C:27](=[O:29])[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:16])[C:19]#[N:20])=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Agent: CC(C#N)c1ccc(Br)cc1F
Agent: N#CC1(c2ccc(Br)cc2F)CCC1
Product: CC(C#N)c1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F

Procedure:
The title compound was prepared analogously to 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile in step 3 of example A(236) substituting 2-(4-bromo-2-fluoro-phenyl)-propionitrile from step 1 below in place of 1-(4-bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile. MS (ESI): 437.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]1=[O:10].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][N:2]1[CH:7]=[C:6]([CH:8]([OH:9])[C:12]([F:14])([F:13])[F:11])[CH:5]=[CH:4][C:3]1=[O:10]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cn1cc(C=O)ccc1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc(C(O)C(F)(F)F)ccc1=O
Yield: 45.9 %

Procedure:
According to Reference Example 8-12, by use of 1-methyl-5-formyl-2-(1H)-pyridone (309 mg, 2.25 mmol), (trifluoromethyl)trimethylsilane (666 μL, 45.1 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 225 μL, 0.225 mmol) and tetrahydrofuran (10.0 mL), the mixture was stirred and reacted at room temperature fort hour. Then, purification by column chromatography (ethyl acetate) was performed to give 1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-2(1H)-pyridone (Compound ET) (214 mg, yield: 46%).