Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=[O:16])[CH:13](Cl)[CH3:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.[Li+].[Cl-]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:12](=[O:16])[CH:13]([N:21]2[CH2:22][CH2:23][C:18]([OH:17])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20]2)[CH3:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(Cl)C(=O)c1cc(F)c2c(c1)CC(=O)N2
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C(=O)c1cc(F)c2c(c1)CC(=O)N2)N1CCC(O)(c2ccccc2)CC1
Yield: 36.6 %

Procedure:
A mixture of 7-fluoro-5-(2-chloropropionyl)-2(1H,3H)-indolone (1.0 g, 4.14 mmol), 4-hydroxy-4-phenylpiperidine (0.74 g, 4.17 mmol) and triethylamine (1.2 ml, 8.6 mmol) in anhydrous dimethylformamide was heated to between 70 and 90° C. for 3 hours. The mixture was poured into 1N aqueous LiCl and extracted with two portions of ethyl acetate. The combined organic phase was washed with 1N HCI, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to 1.6 g of a reddish solid. The crude product was purified by flash chromatography on silica gel (2×4 inches {50×100 mm}, 50% ethyl acetate/hexane eluent) to yield 0.58 g of the desired product. This product was further purified by recrystallization from acetonitrile/ether to give 0.2 g of light yellow solid; m.p. 197°-199.5° C. NMR (DMSO-d6) 11.25 (s, 1H), 7.90 (d, J=11.6 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J=7.2 Hz, 2H), 7.28 (t, J=7.4 Hz, 2H), 7.17 (t, J=7.2 Hz, 1H), 4.76 (s, 1H), 4.25 (q, J=6.6 Hz, 1H), 3.66 (s, 2H), 2.88-2.63 (m, 2H), 2.60-2.55 (m, 1h), 2.49-2.38 (m, 1H), 1.88 (dt, J=12.2, 4.3 Hz, 1H), 1.77-1.49 (m, 3H), 1.16 (d, J=6.6 Hz, 3H). The mother liquors were rechromatographed to afford another 0.15 g of product for a total yield of 0.35 g (22%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 120 h

Procedure:
A mixture of 3,4-dinitro-benzoylchloride (24 g, 93.7 mmol) in 80 mL THF was added to a stirred mixture of aniline (10.4 mL, 112 mmol) and TEA (15.6 mL, 112 mmol) in 300 mL THF under nitrogen. After stirring for 5 days, the mixture was filtrated, washed with THF and evaporated to dryness. The residue was taken up in diethyl ether, filtrated and dried at 55° C.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:11]>O1CCOCC1>[CH2:8]([O:7][C:5]([C:4]1[N:11]([CH2:10][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:3]=[N:2][N:1]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C#N
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: C1COCCO1
Product: CCOC(=O)Cn1nnnc1C(=O)OCC

Procedure:
A solution of ethyl azidoacetate (6.45 grams, 50 millimoles, 98.5 percent pure) and ethyl cyanoformate (10.0 grams, 100 millimoles) in 30 milliliters of dioxane was heated to reflux for 70 hours to insure complete reaction. The resulting reaction mixture was concentrated under vacuum to give 10.0 g. (88%) of the product as an oil. NMr indicated that the oil product was 88 percent pure; therefore, the actual yield from the reaction was 77 percent.
Reaction SMILES: O.NN.[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13]C)=[O:12]>C(O)C>[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)Cc1cccn1C
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1cccc1CC(=O)O
Yield: 99.9 %

Procedure:
Hydrazine monohydrate (65 ml) was added dropwise to a solution of methyl 1-methyl-1H-pyrrole-2-acetate (0.326 mol) in ethanol (300 ml) and the mixture was refluxed for 4 hours. The mixture was evaporated till dryness. The residue was taken up in dichloromethane and an aqueous potassium carbonate solution (10%) and extracted with dichloromethane. The organic layer was dried (MgSO4) and evaporated. The residue (48.8 g) was taken up in 1,1'-oxybisethane and the precipitate was filtered off, yielding 45.3 g (90%) of 1-methyl-1H-pyrrole-2-acetic acid, hydrazine (interm. 7).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:18][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(O)n2nc(C)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc(Cl)n2nc(C)nc2n1
Temperature: 0 °C
Yield: 33.7 %

Procedure:
To an ice-cooled mixture of 30.5 g (0.15 mole) of 7-hydroxy-5-methoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine and 300 ml of phosphorus oxychloride, 18.6 ml (0.15 ml) of N,N-dimethylaniline was added dropwise over 5 minutes and the mixture was stirred under reflux for 1 hour, followed by concentration. The residue obtained was dissolved in 300 ml of chloroform and washed with water, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated and n-hexane was added to the set residue. The crystals were collected by filtration and dried to obtain 11.19 g of the title compound (Yield: 33.7%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH2:14])=[S:13]>C(O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[S:13][CH:5]=[C:3]([CH2:2][Cl:1])[N:14]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(C(N)=S)cc1OC
Solvent: CCO
Product: COc1ccc(-c2nc(CCl)cs2)cc1OC
Yield: 59.1 %

Procedure:
1.5 g of 1,3-dichloroacetone and 2.3 g of 3,4-dimethoxythiobenzamide were suspended in 100 ml of ethanol. The suspension was heated for 3 hours to complete the reaction. The solvent was removed by distillation. The residue was purified by silica gel column chromatography to obtain 1.86 g of 2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole as a colorless viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:18][C:19]3[CH:20]=[C:21]([B:25]4[O:33]C(C)(C)C(C)(C)[O:26]4)[CH:22]=[CH:23][CH:24]=3)=[C:7]([CH3:17])[N:8]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:18][C:19]3[CH:20]=[C:21]([B:25]([OH:33])[OH:26])[CH:22]=[CH:23][CH:24]=3)=[C:7]([CH3:17])[N:8]2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Sc2cccc(B3OC(C)(C)C(C)(C)O3)c2)c2ccc(Cl)cc2n1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Sc2cccc(B(O)O)c2)c2ccc(Cl)cc2n1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(6-Chloro-2-methyl-1-pyridin-3-yl-1H-indol-3-ylsulfanyl)-phenylboronic acid pinacol ester (0.400 g, 0.86 mmol) was dissolved in THF:MeOH (1:1, 10 mL) and sodium hydroxide (2.5 mL of 1.0M aqueous solution, 2.5 mmol) was added. The reaction was stirred at room temperature overnight then submitted to aqueous workup and purified by preparatory HPLC (30-100% ACN in H2O) to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CN1C(=O)CCC1>[CH2:21]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: COc1ccc2c(Cc3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1
Reaction time: 0.17 h

Procedure:
To a solution of (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (0.2543 g 1 equiv) in dry THF (2 ml) and NMP (0.2 ml) under Argon was added Fe(acac)3 (acac=acetylacetonate) (46.8 mg 0.15 equiv). The mixture was stirred for 10 min, and then Benzylmagnesium chloride (2M in THF, 0.792 ml 1.8 equiv) was added dropwise. The mixture was stirred at room temperature overnight. The product was purified by HPLC to give 11.5 mg of solid. LC-MS: m/e 345 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[CH3:28])=[O:8]>CO.CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[CH3:28])=[O:8]
Reactant: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(N)ccc2n1Cc1ccccc1
Reaction time: 24 h
Yield: 104.3 %

Procedure:
To a solution of 1-benzyl-2-methyl-5-nitro-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 45, 97 mg, 0.22 mmol) in MeOH (20 ml) and EtOAc (20 ml) was added Pd—C (10%, 47 mg, 0.045 mmol). The reaction was stirred under hydrogen for 24 h, filtered through Celite, washed with MeOH-EtOAc (1:1) to yield 5-amino-1-benzyl-2-methyl-1H-indole-3-carboxylic acid, 3,4-difluorobenzylamide (Compound 46) as a white solid (93 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(Br)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Clc1c(Br)cnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
5-Bromo-4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4.1 g, 10.57 mmol, see Example 1) was placed in THF (80 mL) at room temperature. TBAF (1.1 equivalents) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then poured into water and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude solid. The solid was then suspended in 10:1 hexanes:DCM, and filtered to give the solid product 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (2.20 g, 89.9% yield).
Reaction SMILES: Cl[C:2]1N=C2C(=CC=1OCC)C=C1N2C(C)CNC1.[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][OH:45])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[H-].[Na+].CI>>[C:19]([O:23][C:24]([N:26]1[CH2:38][C@@H:37]([CH3:39])[N:36]2[C@H:28]([CH2:29][C:30]3[C:35]2=[N:34][C:33]([C@H:40]([O:42][CH3:43])[CH3:41])=[C:32]([CH2:44][O:45][CH3:2])[CH:31]=3)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOc1cc2cc3n(c2nc1Cl)C(C)CNC3
Reactant: CO[C@H](C)c1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COCc1cc2c(nc1[C@@H](C)OC)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-7-hydroxymethyl-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and methyl iodide.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([NH:1][CH:2]=[C:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:21]
Reactant: COC(=O)C(=CN)C(C)=O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=CNC(=O)C(Cl)(Cl)Cl)C(C)=O

Procedure:
Methyl 2-aminomethylene-3-oxobutanoate (1.4 g) in methylene chloride (20 ml) was treated with triethylamine (2.0 ml) and trichloroacetyl chloride (2.0 ml) while stirring at 20°-25° C. The mixture was stirred for 4 hours at 20° C. to give a solution of the title compound, which was used immediately to prepare the dihydropyran of Example 15 without isolation.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[C:15]([Br:28])=[C:16]([C:25]([OH:27])=[O:26])[C:17]([Br:24])=[C:18]([C:22]=1[Br:23])[C:19]([OH:21])=[O:20]>O1CCOCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[C:22]([Br:23])=[C:18]([C:19]([OH:21])=[O:20])[C:17]([Br:24])=[C:16]([C:15]=2[Br:28])[C:25]([OH:27])=[O:26])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1c(Br)c(C(=O)O)c(Br)c(C(=O)O)c1Br
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: O=C(Nc1c(Br)c(C(=O)O)c(Br)c(C(=O)O)c1Br)c1ccc([N+](=O)[O-])cc1

Procedure:
50 9 of para-nitrobenzoic acid chloride and 75 g of 5-amino-2,4,6-tribromoisophthalic acid in 400 ml of dioxane are maintained for 18 hours at the reflux temperature. After cooling, the precipitate is filtered off, washed with 50 ml of dioxane and dried.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9](=O)[NH:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])=[N:6][C:5]=2[N:21]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:21][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)[nH]c(=O)c2s1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reaction time: 0.33 h
Yield: 31 %

Procedure:
The product of step (c) (10.0 g) was suspended in phosphoryl chloride (55 ml). N,N-dimethylaniline (5.5 ml) added slowly and reaction mixture heated at reflux for 2 hours. Allowed to cool, then poured on to ice with vigorous stirring; temperature was not allowed to go above 45° C. (ice added). After approximately 20 minutes the temperature stabilized at 30° C. The solid that formed was collected by filtration and washed with water. Purified by column chromatography (EtOAc to 5% MeOH in EtOAc) to give 3.34 g of product. 31% yield.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[N:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1COCC1.O>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[N:31]=[N:32][C:33]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)CO
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nn3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a stirred solution of neopentyl alcohol (105 mg, 1.19 mm ol) in THF (5 mL) at ambient temperature add sodium hydride (31 mg, 95%, 1.19 mmol) and continue stirring for 3 h at ambient temperature. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (315 mg, 0.59 mmol) in THF (1 mL) and continue stirring overnight at ambient temperature and then at 60° C. for 1 h. Dilute with water, extract the reaction mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[6-(2,2-dimethyl-propoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (81 mg, 28%). MS (APCI+) m/z: 492 (M+H)+, 392 (M+H−Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 392 (M+H)+, m/z: 322 M+H−C5H11)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[Cl:20][C:21]1[C:22]([NH2:29])=[N:23][C:24]([NH2:28])=[N:25][C:26]=1Cl.CCN(CC)CC>CN(C=O)C>[Cl:20][C:21]1[C:26]([NH:19][C@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])=[N:25][C:24]([NH2:28])=[N:23][C:22]=1[NH2:29]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
To a 10 mL vial were added (S)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (100 mg, 0.384 mmol), 5,6-dichloropyrimidine-2,4-diamine (68.8 mg, 0.384 mmol) and Et3N (0.11 mL, 0.77 mmol) in DMF (3 mL). The resulting yellow solution was heated to 90° C. and stirred overnight. The reaction mixture was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium formate). The fractions containing the desired product were combined and lyophilized to give the title compound as a white solid (22 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.41 (m, 3 H), 2.70-2.82 (m, 2 H), 3.00-3.15 (m, 3 H), 3.69-3.93 (m, 10 H), 5.55-5.67 (m, 2H), 5.79-5.89 (m, 1 H), 5.89-5.96 (m, 2 H), 6.11-6.22 (m, 1 H), 6.47-6.57 (m, 1 H), 7.49-7.59 (m, 1 H), 7.75-7.84 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H23ClN8O, 403. found 403.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](F)=[C:9]([F:14])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN(C)C(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:9]([F:14])[CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(F)c(F)c1)C1CC1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(c1ccc(N2CCNCC2)c(F)c1)C1CC1
Temperature: 80 °C
Yield: 52.8 %

Procedure:
To 4-cyclopropanesulfonyl-1,2-difluoro-benzene (40 mg, 0.18 mmol) in 5 ml N,N-dimethylacetamide was added piperazine (47 mg, 0.55 mmol) and the mixture was heated at 80° C. for 90 min. The mixture was then concentrated in vacuo to afford the tide compound (27 mg, 52%) as a brown solid. MS (ISP): 285.0 MH+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=O)=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.Cl.[O:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.[Na]>ClCCl>[O:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:17][C:15]2[S:14][C:13]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=4)[C:9](=[O:22])[N:10]4[N:21]=[CH:20][N:19]=[C:11]4[C:12]=3[CH:16]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)sc32)cc1
Reactant: C1CNCCOC1
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCCOCC4)sc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
8-((1,4-oxazepan-4-yOmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (29). To a mixture of 6-(4-methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde (50 mg, 0.15 mmol) and 1,4-oxazepane hydrochloride (30 mg, 0.22 mmol) in dichloromethane (2 ml) was added triethylamine (25 μl, 0.18 mmol). After 5 minutes of stifling, sodium triacetoxyhydroborate (47 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature. After 4 hours, the mixture was concentrated under reduced pressure. The resulting residue was taken up in DMSO (2 mL), filtered and purified directly by reverse phase chromatography to yield the above product (33 mg, 41%) as a white solid.
Reaction SMILES: O[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O.CN(C)C1C=CC=CC=1>>[Cl:19][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[CH:3]=1
Reactant: COC(=O)c1c(O)cc(=O)n2c1CCCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1c(Cl)cc(=O)n2c1CCCC2

Procedure:
Methyl 8-hydroxy-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7a, 2 g, 9.52 mmol, 1 eq) was suspended in phosphorous oxychloride (5.3 ml, 57 mmol, 6 eq) and dimethylaniline (242 μl, 1.9 mmol, 0.2 eq) under nitrogen and stirred at RT for 16 h. The solution was concentrated in vacuo, quenched with ice and made basic with sat. NaHCO3 solution. The aqueous solution was concentrated in vacuo and the residue triturated in 20% MeOH/DCM. Inorganic salts were removed by filtration and the filtrate evaporated to dryness. The resulting solid was purified by flash chromatography using 75% EtOAc/DCM as eluent to give the title compound as a white solid. (1.43 g, 63%) [M+H] calc'd for C11H12ClNO3, 242. found, 242
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:11]2[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=2[CH:9]=1)=O)(C)(C)C.[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>>[CH3:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:6]([C:8]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[C:11]3[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:5])=[N:37][CH:38]=1
Reactant: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Reactant: Cc1ccc(N)nc1
Solvent: O=C(O)C(F)(F)F
Product: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccc(C)cn3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (228a) and 5-methyl-pyridin-2-ylamine. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.59 Hz, 1 H) 8.09 (s, 1 H) 7.92 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.65 (dd, J=8.59, 2.02 Hz, 1 H) 7.19 (s, 1 H) 7.13 (s, 2 H) 7.09-7.11 (m, 1 H) 3.43-3.53 (m, 2 H) 3.41 (s, 3 H) 3.16 (d, J=16.42 Hz, 1 H) 3.06-3.10 (m, 3 H) 2.80 (d, J=16.67 Hz, 1 H) 2.34 (s, 3 H) 1.48 (s, 3 H); LCMS for C25H26N2O6S m/z 483.00 (M+H)+; Anal. Calcd. for C25H26N2O6S.0.37 TFA: C, 58.95; H, 5.18; N, 5.34. Found: C, 58.92; H, 5.07; N, 5.34.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.[CH3:13][C:14]1[C:19]([NH2:20])=[C:18]([CH3:21])[CH:17]=[C:16]([CH3:22])[N:15]=1>C(#N)C>[Cl:12][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH:20][C:19]2[C:14]([CH3:13])=[N:15][C:16]([CH3:22])=[CH:17][C:18]=2[CH3:21])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(C)c(N)c(C)n1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CC#N
Product: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2[N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A solution of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg, 1.00 mmol) in 2.5 ml of acetonitrile was treated with 2,4,6-trimethyl-3-amino-pyridine (273 mg, 2 mmol) stirred at room temperature 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give red residue. The residue was purified through silica gel column chromatography using chloroform to 6% methanol in chloroform as eluent to give the title compound (110 mg, 36%) as an orange oil. 1H NMR (CDCl3) δ 8.78 (brs, 1H), 6.97 (s, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H) ppm.