Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>ClCCl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=3[CH3:22])=[CH:23][CH:24]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Yield: 40.6 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.0 g, 3.10 mmol) was added, and dissolved in 15 mL dichloromethane. Triethylamine (1.3 mL, 9.34 mmol) was added, in an ice bath a dichloromethane solution dissolving 4-chlorobenzoyl chloride (0.544 g, 3.11 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 4 h. It was filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 0.580 g, at a yield of 40.6%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)=[C:12]([NH:14][C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[CH:13]=1)=[O:7].C(N(C(C)C)CC)(C)C.[CH3:44][C:45]([CH3:51])([CH2:49][CH3:50])[C:46](Cl)=[O:47]>C(Cl)Cl>[CH3:44][C:45]([CH3:51])([CH2:49][CH3:50])[C:46]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:26][CH2:27]2)=[C:12]([NH:14][C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[CH:13]=1)=[O:7])=[O:47]
Reactant: CNCCNC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)c1
Reactant: CCC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)C(=O)N(C)CCNC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)c1
Temperature: 12.5 °C
Reaction time: 4 h

Procedure:
Furan-2-carboxylic acid [5-{2-[(2,2-dimethyl-butyryl)-methyl-amino]-ethylcarbamoyl}-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (compound no. 133) was prepared as follows: To a solution of furan-2-carboxylic acid [5-(2-methylamino-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (0.04 g, 0.086 mmol) and diisopropylethylamine (0.5 mL) in CH2Cl2 (2.0 mL), 2,2-dimethyl butyryl chloride (0.173 mmol) was added at 0° C., and the reaction was stirred at 0-25° C. for 4 h. Reaction was diluted with CH2Cl2 and washed with a solution of saturated NaHCO3. Organic layer was concentrated and dissolved in ACN and purified on preparative HPLC using water/MeOH (0.1% TFA) as eluent to give the product (0.01 g, 21% yield).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[NH:12][CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.CS(O[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)(=O)=O>O>[Cl:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][N:12]([C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:13])[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CS(=O)(=O)OCCc1ccc(Cl)c(Cl)c1
Reactant: CN[C@@H]1CCCC[C@@H]1N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCc1ccc(Cl)c(Cl)c1)[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 60 °C

Procedure:
(±)-cis-2-Pyrrolidinyl-N-methylcyclohexylamine (3 gm) was combined with anhydrous dimethylformamide (70 ml) and warmed to 60° C. 2-(3,4-dichlorophenyl)ethyl methanesulfonate (14 gm) was added to the warm amine solution over 3 days. The reaction mixture was diluted to 500 ml with water and extracted with chloroform. The combined extracts were washed with water and treated with a solution of hydrogen bromide in methanol. The solution was concentrated on a rotary evaporator and the residual dimethylformamide removed by distillation under high vacuum. The residue was triturated with 2-propanol to provide a white solid. The solid was recrystallized from 2-propanol. Analytical data are reported in Table I.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][CH2:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.O>C(O)(=O)C>[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[CH2:18][CH2:17][C:16]1[NH:15][C:3]2=[CH:4][C:5]3[C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=3[CH:10]=[C:2]2[N:1]=1
Reactant: CN1C(=O)C(C)(C)c2cc(NC(=O)CCc3nc4ccccc4[nH]3)c(N)cc21
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)c2cc3[nH]c(CCc4nc5ccccc5[nH]4)nc3cc21
Yield: 43.4 %

Procedure:
A solution of N-(6-amino-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-3-(1H-benzoimidazol-2-yl)-propionamide (218 mg) in acetic acid (6 ml) is heated under reflux for 3 h. After re-cooling, water is added and the mixture is extracted with EtOAc (3×30 ml). The combined organic layer is washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo to give the desired compound (90 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=4)[CH:3]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cncc(Br)c3)nc(C3CC3)c2)cc1
Product: Nc1ccc(-c2cncc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)c2)cn1

Procedure:
The title compound was prepared from 5′-bromo-6-cyclopropyl-4-(4-trifluoromethylphenyl)-[2,3′]bipyridinyl (example E.25) (0.15 g, 0.36 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.087 g, 0.40 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 51%). MS (ISP) 433.3 [(M+H)+]; mp 207-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: Cc1cccc(Cl)c1C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: Cc1cccc(Cl)c1C(=O)N=C=O
Yield: 86.7 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-chloro-6-methylbenzamide (1.0 g, 5.9 mmol), oxalyl chloride (0.894 g, 7.1 mmol) and EDC (20 mL) to afford 1.00 g of the desired product.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:16])=O.C(N(CC)CC)C>CO>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][NH:11][C:14]1([CH3:16])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)NCc1ccccc1
Reactant: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)NCC(=O)N1Cc1ccccc1

Procedure:
To a solution of N1-benzylglycinamide (3.00 g, 14.95 mmol) in MeOH (25 mL) were added acetone (5.50 mL, 74.75 mmol) and triethylamine (1.67 mL, 11.96 mmol). The solution was stirred and heated to reflux overnight under an atmosphere of nitrogen. The solvent was removed in vacuo, and the resulting orange oil was purified by flash column chromatography on silica gel using a gradient elution of 0-7% (MeOH/NH3)/CH2Cl2. Collection and concentration of the appropriate fractions afforded the product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 5H), 4.44 (s, 2H), 3.55 (s, 2H), 1.26 (s, 6H); ES MS (M+1)=205.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)(O)[O-].[Na+].O>COCCOC.O>[CH3:27][N:28]([CH3:38])[C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N(C)C)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 47.7 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (53.3 mg, 0.32 mmol) in DME/water (3 mL:1 mL). PdCl2 (dppf)-CH2Cl2 adduct (8.7 mg, 0.011 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and the insoluble green mixture was irradiated (microwave) at 150° C. for 20 min. After cooling, 2 mL of water was added to the dark green mixture and solids that precipitated were filtered. EtOAc was added, the mixture was heated and some hexanes were added. Solids were filtered, dissolved in DCM/MeOH (1:1), and filtered through a pad of silica gel and the filtrate was evaporated. The residue was dissolved in DCM and purified by SiO2 chromatography (eluent: gradient of 0 to 90:10 DCM/MeOH) to afford a residual oil that was triturated with EtOH/EtOAc (1:1). The resultant solid was filtered and dried to afford the title compound (46 mg, 45%) as a yellow solid. LCMS E-S (M+H)=460.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1 H), 9.02 (d, J=2.27 Hz, 1 H), 8.87 (t, J=4.67 Hz, 1 H), 8.36 (dd, J=8.84, 2.53 Hz, 1 H), 8.31 (s, 1 H), 8.08 (s, 1 H), 6.79 (d, J=8.84 Hz, 1 H), 5.91 (s, 1 H), 5.25-5.34 (m, 1 H), 4.40 (d, J=4.80 Hz, 2 H), 3.12 (s, 6 H), 2.23 (s, 3 H), 2.13 (s, 3 H), 1.53 (d, J=6.57 Hz, 6 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2>>[F:33][C:31]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([CH3:34])=[N:28]2)=[C:23]([O:22][CH2:21][CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[CH:32]=1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Reactant: Cc1ccc2c(OCCBr)cc(F)cc2n1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cc(F)cc2n1

Procedure:
The title compound was prepared from 8-piperidin-4-ylmethyl-4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-7-fluoro-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1cccs1

Procedure:
Following the procedure described in the preceeding example but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-thienylsulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([CH2:9][CH2:10][S:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][O:15][C:14]2[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=4)[N:30]=3)=[CH:26][C:13]1=2)(=O)[NH2:7].[OH-].[Na+]>CN(C)C=O>[Cl:39][C:33]1[CH:32]=[C:31]2[C:36]([CH:37]=[CH:38][C:29]([CH2:28][O:27][C:25]3[CH:24]=[CH:23][C:14]4[O:15][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[CH:12]([S:11][CH2:10][CH2:9][C:6]#[N:7])[C:13]=4[CH:26]=3)=[N:30]2)=[CH:35][CH:34]=1
Reactant: NC(=O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#CCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
Under ice cooling and stirring, 1.35 ml of phosphorus oxy-chloride was added dropwise over 40 minutes to 1.78 g of 11-(2-carbamoylethylthio)-2-(7-chloroquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 63 dissolved in 14 ml of dimethylformamide and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added 250 ml of a 1% sodium hydroxide aqueous solution, crystals precipitated were collected by filtration and the crystals were dissolved in chloroform. After this chloroform solution was washed with water and dried over anhydrous sodium sulfate, the solvent was removed to obtain 1.62 g of the title compound.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[CH3:18][N:19]([CH2:21][C:22](Cl)=[O:23])[CH3:20].CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:11][C:7]1[C:6]2[N:5]([C:4]([CH:12]3[CH2:17][CH2:16][N:15]([C:22](=[O:23])[CH2:21][N:19]([CH3:20])[CH3:18])[CH2:14][CH2:13]3)=[N:3][C:2]=2[I:1])[CH:10]=[CH:9][N:8]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(I)c12
Reactant: CN(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2nc(I)c3c(N)nccn23)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of 1-iodo-3-piperidin-4-yl-imidazo[1,5-a]pyrazin-8-ylamine (1.000 g, 2.91 mmol) and dimethylamino-acetyl chloride (0.38967 g, 3.20 mmol) in DMF (10.00 mL) was added DIEA (2.58 mL, 14.57 mmol) at 0° C. The resulting mixture was stirred at rt. overnight. The mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (50 ml×3). The extracts were combined, dried (Na2SO4). Solvent was then removed under reduced pressure and the resulting residue was used for next step without further purifications. MS (ES+): m/z 428.74 [MH+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:22]I.O>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:22])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
The title compound was prepared from biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide (0.4 g), methyl iodide (0.2 mL) and K2CO2 (0.5 g) in dimethylformamide (20 mL). The mixture was stirred at room temperature for 4 hours, poured into water and extracted with diethyl ether. The organic phase was repeatedly washed with water and evaporated to give the title compound as a white solid (80%). δC (DMSO, 62.9 MHz): 23.7, 29.5, 34.5, 49.6, 60.2, 127.1, 127.2, 127.6, 128.6, 129.2, 135.8, 138.4 and 144.3. δH (DMSO, 250 MHz): 1.45 (4H, m), 2.68 (3H, s), 2.97 (2H, t, J 7.0), 3.40 (2H, m), 7.49 (3H, m), 7.75 (2H, d, J 7.0), 7.83 (2H, d, J 8.5) and 7.91 (2H, d, J 8.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]([F:19])([F:18])[F:17].[CH:21]1([CH:24]=O)[CH2:23][CH2:22]1>[N+](C1C=CC=CC=1)([O-])=O>[CH:21]1([C:24]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:17])[F:18])[C:7]3=[N:6][C:5]([OH:20])=[CH:4][CH:3]=[C:2]3[N:1]=2)[CH2:23][CH2:22]1
Reactant: O=CC1CC1
Reactant: Nc1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Solvent: O=[N+]([O-])c1ccccc1
Product: Oc1ccc2nc(C3CC3)n(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 120 °C
Yield: 10.3 %

Procedure:
5-Amino-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (0.10 g, 0.32 mmol) was dissolved in nitrobenzene (0.5 mL). Cyclopropanecarbaldehyde (0.044 g, 0.64 mmol) was added. The reaction mixture was heated to 120° C. overnight. After cooling, hexanes was added to the reaction mixture to form a precipitate. The precipitate was collected, washed with hexanes, and purified via HPLC to give the title compound (11 mg). LCMS m/z=336.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.35 (m, 4H), 2.03 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 7.71 (m, 2H), 7.83 (m, 2H), 7.83 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5].[CH3:20][O-].[Na+].CI.[Cl-].[NH4+]>CO>[CH3:1][S:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([CH3:20])[C:4]#[N:5]
Reactant: C[O-]
Reactant: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSC(C)(C#N)c1cccc(C(=O)c2ccccc2)c1
Yield: 73 %

Procedure:
433 mg of alpha-(methylthio)(m-benzoylphenyl)-acetonitrile was dissolved in 2 ml of anhydrous methanol. The solution was stirred in an atmosphere of argon under ice cooling. Then, 0.65 ml of a 2.5 M methanol solution of sodium methoxide was added, and then 0.15 ml of methyl iodide was added dropwise. Under ice cooling, the mixture was stirred for 1 hour, and an aqueous solution of ammonium chloride (0.5 g/30 ml) was added. The mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; methylene chloride) to afford 334 mg (yield 73%) of alpha-(methylthio)-alpha-(m-benzoylphenyl)-propionitrile as a pale yellow oil.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O[NH:9][C:10](=[NH:26])[CH2:11][C:12]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=[CH:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>O>[C:5]([O:4][NH:26][C:10](=[NH:9])[CH2:11][C:12]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=[CH:18]2)[CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:7])[CH3:6]
Reactant: N=C(CC1(n2ccc3cccnc32)CCCC1)NO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)ONC(=N)CC1(n2ccc3cccnc32)CCCC1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
Acetic anhydride (11.2 mL, 118.61 mmol) was added to N-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetamidine (400) (1.8 g, 6.98 mmol) and stirring was continued for 3 h at room temperature (TLC, ethyl acetate, Rf=0.5). Water (50 mL) was added, and the mixture was basified to pH 8 by solid NaHCO3 and extracted with ethyl acetate (3×50 mL). The organic phase was thereafter dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 2-(1-{1H-pyrrolo[2,3-b]pyridin-1-yl}cyclopentyl)ethanimidamido acetate (401) (1.7 g, 81%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>O>[C:14]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1)(=[O:16])[CH3:15]
Reactant: Nc1cccnc1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cccnc2)cc1

Procedure:
To a solution of 23.7 g. of 3-aminopyridine in 400 ml. of pyridine is added 55 g. of 4-acetylbenzenesulfonyl chloride and the resulting solution is stirred at room temperature for 24 hours. The solution is poured into 1 l. of water and the mixture is cooled to 0°-5° C. The precipitate of 4-acetyl-N-(3-pyridyl)benzenesulfonamide is collected by filtration, washed with water and dried; m.p. 182°-183° after crystallization from ethanol.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@@H:35]([CH3:45])[CH2:36][CH2:37][NH:38][CH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1.C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:4])[N:34]4[C@@H:35]([CH3:45])[CH2:36][CH2:37][N:38]([CH:39]5[CH2:44][CH2:43][S:42][CH2:41][CH2:40]5)[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: C[C@H](N)CCNC1CCSCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1CCN(C2CCSCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N12
Yield: 49.2 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (25 mg, 0.055 mmol) and free based [(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (48 mg, 0.26 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (16 mg, 49%) as a film. This material was debenzylated in a second step in a manner similar to Z-26 to give (4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (8 mg, 59%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.30 (d, J=7.2 Hz, 3H), 1.53-1.58 (m, 1H), 1.72-2.10 (m, 5H), 2.56-2.76 (m, 5H), 2.84-2.87 (m, 2H), 4.18 (dd, J=2.8, 14.0 Hz, 1H), 4.26 (dd, J=3.4, 14.2 Hz, 1H), 4.92-4.97 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.36 (m, 2H), 8.31 (s, 1H), 10.48 (m, 1H), 12.48 (br, 1H); ES+ MS: 501 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([CH:58]([CH3:60])[CH3:59])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][CH:58]([CH3:60])[CH3:59])=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2-isocyanatopropane as starting materials in 58% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.40 (m, 2H), 9.05 (s, 1H), 8.33 (m, 2H), 8.20 (s, 1H), 7.63 (m, 1H), 7.30 (m, 1H), 7.09 (m, 1H), 6.09 (m, 1H), 3.92 (m, 2H), 3.75 (m, 1H), 2.97 (s, 4H), 2.62 (m, 2H), 2.28 (m, 2H), 1.91 (m, 1H), 1.64 (m, 2H), 1.09 (m, 2H), 1.00 (d, 6H). LCMS for C28H34ClN8O2 (M+H)+: m/z=549.2.