Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:17]([C:19]1[N:20]=[C:21]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=1)[NH2:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[O:16]=[C:14]([NH:18][NH:17][C:19]1[N:20]=[C:21]2[CH:27]=[CH:26][N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]2=[N:23][CH:24]=1)[CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 111.9 %

Procedure:
To a solution of (S)-3-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.756 g, 3.30 mmol, AstaTech) and 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (1.0 g, 3.3 mmol, Example #1, Step D) in DMF (33 mL) was added TEA (1.38 mL, 9.89 mmol) followed by the addition of HATU (1.25 g, 3.30 mmol). The resulting mixture was stirred at ambient temperature for about 15 h then concd under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with water (100 mL). The organic portion was separated, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure to give (S)-tert-butyl 3-(2-oxo-2-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinyl)ethyl)pyrrolidine-1-carboxylate as a sticky brown solid (1.90 g, 100%). This material was used without further purification: LC/MS (Table 1, Method c) Rt=1.38 min; MS m/z: 515 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:26]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (0.150 g; 0.580 mmol) in N,N-dimethylformamide (2 mL) is added 4-chlorophenylsulfonyl chloride (0.122 g; 0.580 mmol) and triethylamine (0.243 mL; 1.740 mmol). The mixture is stirred at room temperature overnight. After this time, the mixture is diluted with water and extracted with ethyl acetate. The combined organics are washed with aqueous saturated sodium bicarbonate solution, 1N hydrochloric acid, and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material is purified by preparative HPLC to afford title compound. ESI m/z 412 [M+NH4]+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[O:41]>O1CCCC1>[CH3:38][N:39]([CH3:43])[C:40]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)=[O:41]
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)N(C)C)CC4)nc12
Yield: 92.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.012 g dimethylcarbamoyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.04 g (92%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid dimethylamide as yellow solid; MS (ISP): m/e=457 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([CH:31]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Reactant: O=Cc1ccc(-c2ccc(F)cc2)s1
Agent: NCCC(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(F)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.100g, 0.378 mmol) and 5-(4-fluorophenyl)thiophene-2-carbaldehyde (0.078 g, 0.378 mmol) in acetic acid 5 mL is added β-alanine (3.37 mg, 0.038 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.125 g, 0.276 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.71 (m, 2H), 7.52 (d, J=4.5 Hz, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.16 (m, 7H), 6.69 (s, 1H), 5.66 (dd, J=11.4, 5.1 Hz, 1H), 3.69 (dd, J=14.4, 11.7 Hz, 1H), 3.51 (dd, J=10.5, 5.1 Hz, 1H). MS (ES−, m/z): 451.4 (M−−1, 45.0).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][CH:10]2C#N)=O)=[CH:5][CH:4]=1.F[B-](F)(F)F.[H+].[C:28]([C:34]([O:36][CH3:37])=[O:35])#[C:29][C:30]([O:32][CH3:33])=[O:31]>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[N:9]3[C:10]([S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=43)=[C:29]([C:30]([O:32][CH3:33])=[O:31])[C:28]=2[C:34]([O:36][CH3:37])=[O:35])=[CH:20][CH:21]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1ccc(C(=O)N2c3ccccc3SC2C#N)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 3-(4-methoxybenzoyl)-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (5.3 g, 17.9 mmol) in dichloromethane (50 mL) was added dropwise 5 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (7.6 g, 54.0 mmol) in DMF (40 mL) and then warmed at 35° C. for 14 h. The reaction mixture was concentrated in vacuo and the residue was crystallized from methanol to give dimethyl 1-(4-methoxyphenyl)benzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate 1.7 g (24%); mp 167-168° C. 1H NMR (DMSO-d6) δ 3.63 (3H, s, COOMe), 3.82 (3H, s, COOMe), 3.86 (3H, s, Me), 6.84-6.86 (1H, m, ArH), 7.12 (2H, d, J=8.4 Hz, 2×ArH), 7.28-7.32 (1H, m, ArH), 7.37-7.40 (1H, m, ArH), 7.48 (2H, d, J=8.4 Hz, 2×ArH), 8.03-8.05 (1H, m, ArH). Anal. Calcd. for (C21H17NO5S): C, 63.79; H, 4.33; N, 3.54; S, 8.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11].[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].C(Cl)(Cl)Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[O:11][C:26](=[O:27])[O:25]1
Reactant: OC(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1OC(c2ccc(F)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Yield: 78.7 %

Procedure:
A mixture of 500 mg of 2-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol, 530 mg of 1,1'-carbonyldiimidazole and 10 ml of dry chloroform is heated under reflux for 1 hour. Water is added to the reaction mixture, and the chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of silica-gel and eluted with a mixture of methylene chloride and methanol (100:0-98:2 v/v). The eluate is concentrated, and the residue is crystallized from ethyl acetate-isopropyl ether to give 420 mg of 4-(2,4-dichlorophenyl)-5-(4-fluorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals. m.p. 191°-192° C. Yield: 78.7%
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[CH2:11][CH:12]=O>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:11]=[CH:12][N:9]=2)[CH:5]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: O=CCCl
Solvent: CCO
Product: Clc1cc(Br)c2nccn2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 3-bromo-5-chloropyridin-2-amine (10 g, 49 mmol) and chloroacetaldehyde (50% in H2O, 12 mL, 98 mmol) in ethanol (100 mL) was heated at 50° C. overnight. It was then cooled to room temperature and concentrated. Acetone (30 mL) was added to the residue and the resulting mixture was stirred rapidly for 2 h. The resulting solid was collected through filtration and dried to afford 101a as a yellow solid (10.0 g, 89%). MS: [M+H]+ 231. 1H NMR (500 MHz, DMSO) δ 9.20 (s, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.09 (s, 1H)
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Product: Cc1nnc(-c2ccc3occ(-c4ccccc4Cl)c3n2)o1
Yield: 6 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using (2-chlorophenyl)boronic acid instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 6%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:15])=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10](O)=[O:11])=[O:4].C(Cl)(=O)C([Cl:19])=O>ClCCl>[Cl:19][C:10]([C:9]1[C:8]([CH3:14])=[CH:7][C:6]([CH3:15])=[C:5]([CH:13]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cc(C(=O)O)c(C)cc1C
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)Cl)c(C)cc1C
Temperature: 40 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-(methoxycarbonyl)-2,4-dimethylbenzoic acid (compound 255.1, 100 mg, 0.48 mmol) in dichloromethane (10 mL). Oxalyl chloride (80 μL, 0.95 mmol) was added and the resulting solution was stirred for 1 h at 40° C., then concentrated under reduced pressure to obtain the title compound as a white solid (80 mg, 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:26]2[C:31](Cl)=[N:30][CH:29]=[CH:28][N:27]=2)[NH:16][C:17](=O)[CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C(NC(C2CCC2)=O)C2C(Cl)=NC=C[N:49]=2)C=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:27]3[CH:28]=[CH:29][N:30]=[C:31]([NH2:49])[C:26]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Reactant: O=C(CC1CCCCC1)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Product: Nc1nccn2c(CC3CCCCC3)nc(-c3cccc(OCc4ccccc4)c3)c12

Procedure:
N-[(3-Benzyloxyphenyl)-(3-chloropyrazin-2-yl)-methyl]-2-cyclohexyl-acetamide: Prepared according to the procedures for Cyclobutanecarboxylic Acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]Amide, White solid, 1H NMR (CDCl3, 400 MHz) δ 0.88-0.97 (m, 2H), 1.09-1.29 (m, 3H), 1.63-1.82 (m, 6H), 2.11 (d, 1H, J=7.2 Hz), 5.02 (s, 2H), 6.55 (d, 1H, J=7.6 Hz), 6.86-6.94 (m, 3H), 7.03 (d, 1H, J=7.6 Hz), 7.19-7.25 (m, 1H), 7.30-7.40 (m, 6H), 8.32 (d, 1H, J=2.0 Hz), 8.49 (d, 1H, J=2.0 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.[CH3:22][NH:23][CH3:24].O>C(O)C>[CH3:22][N:23]([CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: CNC
Reactant: O=C(c1ccccc1)c1ccc(OCCCCCBr)cc1
Solvent: O
Solvent: CCO
Product: CN(C)CCCCCOc1ccc(C(=O)c2ccccc2)cc1
Yield: 97 %

Procedure:
A solution of 3.0 g of 4-[(5-bromopentyl)oxy]benzophenone in 30 ml of ethanol was heated to 90° in a pressure tube for 1.5 hours with 16 ml of a 33 percent solution of dimethylamine in ethanol. After cooling the mixture was poured into water and extracted three times with ethyl acetate. The organic phases, dried over sodium sulphate, were evaporated and the residue was chromatographed on neutral aluminium oxide (activity grade III) with hexane:ethyl acetate (7:3). There were obtained 2.69 g (97%) of 4-[(5-(dimethylamino)pentyl)oxy]benzophenone as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Yield: 23 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (S)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (91 mg, 23%) was prepared as a tan powder: [α]25D +197.70 (c 1.00, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.51 (br s, 1H), 11.28 (s, 1H), 8.83-8.74 (m, 1H), 8.32-8.25 (m, 1H), 7.65-7.60 (m, 1H), 7.51-7.32 (m, 3H), 7.15-6.98 (m, 2H), 6.43-6.18 (m, 1H), 5.07-4.86 (m, 2H), 4.46-4.21 (m, 3H), 3.73-3.62 (m, 4H), 3.18-2.87 (m, 5H), 2.08-1.88 (m, 3H); MS (ESI) m/e 430 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[C:3]([CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH2:27])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: [BH3-]C#N
Reactant: O=C(Cc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(Cc1ncc(C(F)(F)F)cc1Cl)c1ccccc1

Procedure:
5.6 g (0.0187 mol) of 2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-1-phenylethanone are diluted in 50 mL of methanol. 50 g of molecular sieves 3 Å, 14.4 g (0.187 mol) of ammonium acetate and 2.45 g (0.037 mol) of sodium cyanoborohydride are then consequently added. The pH is adjusted to 5-6 with acetic acid (1 mL). After of 4 days of reaction at room temperature, the medium is filtered and 1M aqueous sodium hydroxide is added until pH=12. 150 mL of ethyl acetate are added, after separation, the aqueous phase is extracted twice with 150 mL of ethyl acetate.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([CH2:2][CH2:3][S:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Product: N#Cc1ccc(S(=O)(=O)CCn2cccn2)cc1

Procedure:
250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with pyrazole to yield 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-pyrazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-pyrazol-1-yl)ethylsulfonyl)-K-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.0 (M)+.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][NH:4][C:5]([CH2:7][O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:6]>CO.Cl.[Pd]>[NH2:16][CH2:15][C:12]1[CH:13]=[N:14][C:9]([O:8][CH2:7][C:5](=[O:6])[NH:4][CH2:3][C:2]([CH3:17])([CH3:1])[CH3:18])=[CH:10][CH:11]=1
Reactant: CC(C)(C)CNC(=O)COc1ccc(C#N)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)CNC(=O)COc1ccc(CN)cn1
Yield: 96.1 %

Procedure:
Bubble nitrogen into a solution of 6-[(2,2-dimethyl-propylcarbamoyl)-methoxy]-pyridine-3-carbonitrile (320 mg, 1.3 mmol) in methanol (26 mL) with 3 drops of concentrated HCl for 10 min. Add 10% Pd/C (Degussa type E101, 64 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the reaction mixture over Celite®, concentrate the filtrate in vacuo and purify by SCX chromatography to obtain the title compound (314 mg, 96%). MS (ES+) m/z: 252 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@:12]2([F:20])[CH3:19])=[C:4]([O:21][CH3:22])[N:3]=1.[C:23](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:32]1[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=1)[C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:29][O:28][C:27]1[CH:30]=[CH:31][C:24]([C:23]([C:32]2[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:17][CH2:16][C@@H:14]2[C@@H:13]([OH:18])[C@:12]([F:20])([CH3:19])[C@H:11]([N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([NH:1][C:23]([C:24]3[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=3)([C:32]3[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[N:3][C:4]=4[O:21][CH3:22])[O:15]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](O)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (2, 4 g, 12.8 mmol) in anhydrous pyridine (100 mL) cooled at 0° C. was added DMT-Cl portion-wise under nitrogen. The brown solution was stirred at ambient temperature for 24 hours. The mixture was concentrated under reduced pressure to remove most of solvent and sat. NaHCO3 (20 mL) was added. The mixture was diluted with water (150 mL) and EtOAc (120 mL). The organic layer was separated and washed with water (5×120 mL), brine and dried over Na2SO4. After removal of solvent, the residue was purified via column chromatography (20% EA in hexanes to 80% EA in hexanes) to afford 11.6 g of product, 3, as a white foam solid (quantitative yield). 1H-NMR (DMSO-d6): δ 7.94 (s, 1H), 7.39-7.37 (m, 3 H), 7.26-7.14 (m, 17H), 6.84-6.80 (m, 8H), 5.58 (s, 1H), 4.04 (br, 1H), 3.71-3.70 (m, 14H), 3.68 (m, 1H), 3.48 (br, 2H), 3.20 (d, 1H), 0.88 (br, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[N:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nc(Cl)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-chloro-2-methylpyridazin-3(2H)-one following a procedure analogous to that described in Example 1 Step 3. LC-MS Method 2 tR=1.179 min, m/z=422.1; 1H NMR (CDCl3) 1.08 (d, 6H), 1.49 (d, 3H), 2.10 (s, 3H), 2.18 (m, 1H), 2.32-2.41 (m, 1H), 2.83 (m, 1H), 3.79 (s, 3H), 5.63 (m, 1H), 6.90-7.03 (m, 5H), 7.23 (m, 2H), 7.46-7.59 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](O)=[O:37]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=3[CH3:33])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)S(C)(=O)=O

Procedure:
Compound 2 was coupled with 2-methylbenzoic acid by procedure K. LC-MS showed the product had the expected M+H+ of 574. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 8.2 (s, 1H) 8.0 (d, 1H) 7.6 (m, 2H) 7.3 (m, 7H), 6.8 (d, 2H), 4.4 (s, 2H), 3.7 (t, 2H), 3.3 (d, 2H), 3.2 (d, 2H) 2.84 (s, 3H), 2.3 (s, 3H), 1.8 (m, 2H).