Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[N:11]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:12])=[CH:4][CH:3]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 56 %

Procedure:
Using general procedure A, 4-amino-N-benzyl-N-methyl-benzenesulfonamide (Mikhura, I. V.; et al., Russ. J. Org. Chem., 36, 1, 2000, 64-68) (852 mg, 3.09 mmol) and 1-Boc-4-piperidone (677 mg, 3.40 mmol) afforded 4-[4-(benzyl-methyl-sulfamoyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (796 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:14][C:13]2=[N:15][NH:16][C:17](=[O:18])[C:10]3[C:11]4[C:12]2=[C:4]([NH:5][C:6]=4[CH:7]=[CH:8][CH:9]=3)[CH2:3]1.Br[CH2:21][CH2:22][O:23]C1CCCCO1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.O.CO>[OH:23][CH2:22][CH2:21][N:5]1[C:4]2[CH2:3][C:2]([CH3:19])([CH3:1])[CH2:14][C:13]3=[N:15][NH:16][C:17](=[O:18])[C:10]4[C:11]([C:12]=23)=[C:6]1[CH:7]=[CH:8][CH:9]=4
Reactant: CC1(C)CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: BrCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC2=NNC(=O)c3cccc4c3c2c(n4CCO)C1
Temperature: 70 °C
Yield: 69 %

Procedure:
To a solution of 2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (100 mg, 0.39 mmol) in dry DMF (8 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol). K2CO3 (215 mg, 1.6 mmol) was added and the mixture was heated at 70° C. for 11.5 hours. Then water (100 mL) was added to the mixture, which was then extracted with EA (50 mL×3). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated to provide crude yellow oil. Then MeOH (15 mL) was added to the residue, followed by the addition of p-TSA.H2O (100 mg, 0.52 mmol), and the mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the mixture, extracted with EA (50 mL×3). The organic layers were combined, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated The residue was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to give 80 mg (69% yield) of 10-(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one as yellow solid. 1H NMR (DMSO-d6) δ 9.89 (s, 1H), 7.58 (d, 1H, J=8.4 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.15 (dd, 1H, J=7.2, 8.4 Hz), 4.88 (t, 1H, J=5.4 Hz), 4.21 (t, 2H, J=5.4 Hz), 3.65-3.68 (m, 1H), 2.76 (s, 2H), 2.25 (s, 2H), and 1.07 (s, 6H). MS (ESI) m/e [M+1]+ 298.1.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([CH2:19]Cl)[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.CO.[OH-].[Na+].[I-:25].[Na+]>CC(C)=O>[IH:25].[Cl:2][CH2:3][CH:4]1[CH:5]2[C:14]3[C:9]([CH2:8][CH2:7][N:6]2[CH2:19]1)=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3
Reactant: COc1cc2c(cc1OC)C(C(CCl)CCl)NCC2
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C1C(CCl)CN1CC2
Product: I
Reaction time: 48 h

Procedure:
5.1 g (0.015 mole) of 1-[bis(chloromethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride are suspended in 24 ml of acetone. 6.0 ml of methanol containing 10% (0.015 mole) of sodium hydroxide are added to the suspension, whereupon the solution is filtered after 5 minutes. 2.3 g (0.0153 mole) of sodium iodide are added to the filtrate, which is allowed to stand for two days and the crystals separated out are filtered out by glass filter. Crystallization from a mixture of acetone and ether yields the aimed compound in the form of pale-beige crystals with a melting point of 202° to 205° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].FC1C=C(C[C@H](NC(=O)OCC2C=CC=CC=2)[C@H]2CO2)C=C(F)C=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([I:22])[CH:24]=1
Reactant: NCc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Agent: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1cccc(I)c1

Procedure:
tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, PREPARATION 3, 1.75 g, 5.8 mmole) is mixed with isopropanol (30 ml). The reaction flask is charged with 3-iodobenzylamine (VI). The reaction mixture is heated to reflux for 45 minutes, HPLC analysis indicates complete disappearance of the epoxide (V). The reaction mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate (150 ml) and aqueous hydrochloric acid (3%, 35 ml). The organic phase is separated and washed with aqueous hydrochloric acid (3%, 20 ml), bicarbonate, saline and dried over sodium sulfate. Concentration under reduced pressure gives the title compound, M+H=535.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=O.C(N)CCC.[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:26]([N+:23]([O-:25])=[O:24])[CH3:27])[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1ccccc1
Reactant: CC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCN
Product: COc1cc(C=C(C)[N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 25 °C
Yield: 69 %

Procedure:
1.15 g of 3-methoxy-4-phenoxybenzaldehyde, 96 μl of n-butylamine, 10 ml of nitroethane and 5 ml of toluene were mixed and refluxed under heating for 2 hours. The reaction solution was left to cool to room temperature and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 953 mg (yield: 69%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[O:8][C:7]([CH2:26][CH3:27])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[O:6]1)=[O:4].[I:28]Cl.C(=O)(O)[O-].[Na+].COC([C@H]1[C@H](C(OC)=O)OCO1)=O>ClCCl>[CH3:13][O:12][C:10]([C@H:9]1[C@H:5]([C:3]([O:2][CH3:1])=[O:4])[O:6][C:7]([CH:26]([I:28])[CH3:27])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[O:8]1)=[O:11]
Reactant: CCC1(c2ccc3cc(OC)ccc3c2)O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1
Reactant: ClI
Agent: COC(=O)[C@@H]1OCO[C@H]1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1OC(c2ccc3cc(OC)ccc3c2)(C(C)I)O[C@H]1C(=O)OC

Procedure:
A solution of 2 -ethyl-2-(6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester (0.935 g, 2.5 mmol) and of iodine monochloride (0.81 g, 5 mmol) in dichloromethane (5 ml) is kept under nitrogen and at 15° C. for 24 hours. The reaction mixture is poured into a 10% aqueous solution of sodium bicarbonate, and extracted with additional dichloromethane. The combined organic extracts are washed with a 5% aqueous solution of sodium thiosulphate, with water, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by column chromatography (silical gel, eluent hexane:diethyl ether=7:3) gives the diastereoisomeric mixture of 2-(1-iodoethyl)-1-iodoethyl)-2-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid dimethyl ester 15 and 16 in ratio 15:16=60:40 (determined by 1H-NMR).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:9][N:10]([CH2:12][CH2:13][NH2:14])[CH3:11]>C(O)(C)C>[CH3:9][N:10]([CH3:11])[CH2:12][CH2:13][NH:14][C:3]1[N:4]=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CSc1nccnn1
Reactant: CN(C)CCN
Solvent: CC(C)O
Product: CN(C)CCNc1nccnn1

Procedure:
3-Methylthio-1,2,4-triazine (19.1 g, 0.15 mole) and unsym-dimethylethylene diamine (35.2 g, 0.40 mole) are dissolved in 100 ml of isopropyl alcohol and the mixture is heated under reflux in a nitrogen atmosphere for five days. The solvent is removed under reduced pressure and the residue is distilled at 0.5 mm of Hg. 3-(2-Dimethylaminoethylamino)-1,2,4-triazine is collected at 168°-169° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].CC(C)([O-])C.[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCCCCC>CS(C)=O.C(OCC)(=O)C>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reaction time: 24 h
Yield: 105.7 %

Procedure:
To a solution of 3,4-dihydroxy-benzonitrile (1.36 g, 10 mmol) and potassium tert-butoxide (1.5 g, 13 mmol) in dimethylsulfoxide (15 mL) was added benzyl chloride (1.5 mL, 13 mmol) under nitrogen atmosphere at room temperature, and the solution was stirred for 24 hours. Silica gel (100 mL) was added portionwise to the reaction solution for adsorption, a pale yellow oil of 4benzyloxy-3-hydroxy-benzonitrile (2.38 g) was obtained by silica gel column chromatography (hexane:ethyl acetate=7:3), in addition, this was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, then ethyl acetate:methanol=90:10, then 85:15), and 4-benzyloxy-3-hydroxy-benzonitrile (0.588 g, 2.61 mmol, 24.8%) was obtained as a pale yellow solid.
Reaction SMILES: CO[C:3](=[O:5])O.[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[CH2:20][C@@H:19]([CH2:21][OH:22])[CH:18]=[CH:17]2)=C(Cl)[N:8]=1.[OH-].[Na+]>O>[NH2:6][C:7]1[NH:8][C:3](=[O:5])[C:10]2[N:11]=[CH:12][N:13]([C@H:16]3[CH2:20][C@@H:19]([CH2:21][OH:22])[CH:18]=[CH:17]3)[C:14]=2[N:15]=1
Reactant: COC(=O)O
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C=C[C@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2C=C[C@H](CO)C2)c(=O)[nH]1
Temperature: 75 °C

Procedure:
To a 5 mL round-bottom flask equipped with a reflux condenser is added cis-2-amino-6-chloro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purine methylcarbonate as prepared in Example 3 (10 mg, 0.031 mmol), sodium hydroxide (2.5 mg, 0.062 mmol), and deionized water (1 mL). The resultant heterogeneous mixture is heated at 75° C. for 12 hours. The reaction mixture becomes a pale amber solution which is filtered hot through a bed of diatomaceous earth. The pH of the filtrate is adjusted to pH 7 with lN hydrochloric acid. Acetonitrile is added and the solution is concentrated in vacuo to a solid via azeotropic removal of water. The solid is tritriated with 2 mL of methanol and the solution is filtered. The filtrate is concentrated in vacuo to give cis-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-6H-purine-6-one as a white solid which exhibits the following physical data: IR (nujol mull, cm-1) 3500-3600 (br, m), 1725 (m), 1630 (s), 1605 (s); UV (EtOH, nm) λ max =275, 255; λ min =225; and mp 268°-270° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C1(C)C(C)=CC=CC=1>[CH:16]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14])([CH2:18][CH3:19])[CH3:17]
Reactant: CCC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: Cc1ccccc1C
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
A mixture of 4-chloro-3,5-dinitro-o-xylene (140 grams, 0.61 mole), mono-sec-butylamine (184 ml., 1.82 moles), and xylene (1400 ml.) is brought to reflux. After refluxing overnight, the reaction mixture is cooled and filtered. The precipitate is washed with petroleum ether. The filtrate and washings are combined, washed with 500 ml. of 10% hydrochloric acid, and finally with 2 liters of water. The organic layer is separated and dried. Removal of the drying agent and the solvent leaves an orange oil which crystallizes with the addition of petroleum ether. A yellow orange solid (150.6 grams, 86.5%) with melting point 42° C. to 43° C. is collected.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[O:16])=[CH:5][CH:4]=1.[CH2:17]([C:20]1[NH:21][C:22]2[C:28]([CH3:29])=[CH:27][C:26]([C:30]3[N:34]([CH3:35])C4C=CC=CC=4N=3)=[CH:25][C:23]=2[N:24]=1)[CH2:18][CH3:19].CC([O-])(C)C.[K+].[CH3:46][N:47](C)[C:48](=O)C>O>[CH2:17]([C:20]1[N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([CH:15]=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[C:23]2[CH:25]=[C:26]([C:30]3[N:34]=[CH:35][N:47]([CH3:48])[CH:46]=3)[CH:27]=[C:28]([CH3:29])[C:22]=2[N:21]=1)[CH2:18][CH3:19]
Reactant: CCCc1nc2cc(-c3nc4ccccc4n3C)cc(C)c2[nH]1
Reactant: O=Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(=O)N(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 4-bromomethyl-2′-formylbiphenyl (I) (1.2 g, 4.32 mmol), 2-(1-propyl)-4-methyl-6-(1′-methylbenzimidazol-2-yl)benzimidazole (1.1 g, 3.6 mmol) and potassium tert-butylate (0.41 g, 3.6 mmol) in 25 ml of N,N-dimethylacetamide is stirred at room temperature under argon atmosphere for 5 hours. Reaction mixture is poured in 160 ml of water and stirred for 30 minutes. Obtained precipitated solid is filtered off, suspended in 70 ml of water again, and stirred for 1 hour. Crude product is filtered off and dried in vacuum at 40° C. overnight. Yield: 1.37 g.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21](O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].S(Cl)(Cl)=O.[Br:29][CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21]([O:33][CH2:32][CH2:31][CH2:30][Br:29])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCCCBr
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (107 g, 0.32 mol) in CH2Cl2 (520 mL) and DMF (100 mL) was cooled to 0° C. and thionyl chloride (28 mL, 0.39 mol) slowly added. The mixture was stirred at room temperature for 1 hour, then cooled to 5° C. Distilled 3-bromopropanol (35 mL, 3.9 mol) was slowly added, and the solution stirred for 1 hour at room temperature. The solution was then washed with water and the organic layer dried over sodium sulfate and evaporated under reduced pressure. The product was recrystallized from ethyl acetate to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-bromopropoxycarbonyl)-1,4-dihydropyridine (12, mp=146° C.).
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([S:23]([Cl:26])(=[O:25])=[O:24])[C:19]([O:21][CH3:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=O)C.[CH3:27][NH2:28]>>[ClH:26].[ClH:26].[CH3:22][O:21][C:19]1[C:18]([S:23](=[O:24])(=[O:25])[NH:28][CH3:27])=[CH:17][C:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[CH:20]=1
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)C(c1ccccc1)CN(C(C)=O)CC2
Reactant: CN
Product: CNS(=O)(=O)c1cc2c(cc1OC)CCNCC2c1ccccc1
Product: Cl

Procedure:
Following the general procedure of Example 2, 3-acetyl-8-chlorosulfonyl-7-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with methylamine and then with refluxing hydrochloric acid to afford 7-methoxy-8-(N-methylsulfamoyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride and the methoxy compound is treated with refluxing hydrobromic acid to give 7-hydroxy-8-(N-methylsulfamoyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:5]2=[C:4]([C:12]([NH:14][C@@H:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:16]([NH:18][CH3:19])=[O:17])=[O:13])[N:3]=1.CC(C)(C)[C@H](NC(C1N=C(C#CC2C=CC=CC=2)N2CCN(C)CC=12)=O)C(NC)=O.C[Si](Cl)(C)C.C([Mg]Cl)(C)C.[CH:64](=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1COCC1>[CH3:21][C:20]([CH3:23])([CH3:22])[C@H:15]([NH:14][C:12]([C:4]1[N:3]=[C:2]([CH:64]([OH:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[N:6]2[CH2:7][CH2:8][N:9]([CH3:11])[CH2:10][C:5]=12)=[O:13])[C:16]([NH:18][CH3:19])=[O:17]
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C)CC2)C(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: CNC(=O)[C@@H](NC(=O)c1nc(C#Cc2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)c1nc(C(O)c2ccccc2)n2c1CN(C)CC2)C(C)(C)C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
Under a nitrogen atmosphere (S)-3-bromo-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-7-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide (Compound 203) (0.050 g, 0.13 mmol) was dissolved in THF and trimethysilylchloride (0.045 g, 0.41 mmol) was added. The resulting solution was stirred for 3 hours. Isopropylmagnesium chloride solution (2M in THF, 0.27 mL, 0.54 mmol) was added dropwise at 0° C. and the mixture was stirred for 15 minutes, then benzaldehyde (0.028 g, 0.26 mmol) was added at 0° C. and the resulting mixture was stirred cold for 40 minutes. The mixture was quenched at 0° C. with NH4Cl saturated solution, stirred for 10 min and concentrated. The reaction mixture was then extracted repeatedly with 20% i-PrOH/DCM and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by prep LC/MS using 5-95% gradient acetonitrile/water with 0.1% formic acid. The resulting material was filtered through Strata SCX SPE tube to give (0.010 g, 18%) of Compound 295 as a free base. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.43 (s, 3H), 2.75 (m, 5H), 3.69 (m, 1H), 3.88 (m, 2H), 4.09 (m, 1H), 4.32 (s, 1H), 7.53 (t, 2H), 5.97 (m 1H), 7.29 (m, 1H), 7.38 (m, 4H); LCMS (+ESI) m/z 414.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([N:23]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:33][CH:32]=2)[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CCOC(=O)CCCNCc1ccc(OC)cc1
Reactant: CCOC(=O)c1c(Cl)nc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(Cc1ccc(OC)cc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Temperature: 80 °C
Yield: 57.3 %

Procedure:
The mixture of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (7.9 g, 29.88 mmol) and ethyl 4-((4-methoxybenzyl)amino)butanoate (5 g, 19.92 mmol) in DMF (500 mL) and DIPEA (4.6 g, 35.85 mmol) was heated at 80° C. for 2 h. The reaction mixture was then cooled to room temperature and crushed ice was added. The reaction mixture was extracted with EtOAc (3×100 mL), and the combined EtOAc layer was dried over sodium sulphate, filtered and evaporated under reduced pressure to give a residue which was purified by column chromatography (silica gel, gradient 0-5% EtOAc in hexanes) to afford ethyl 4-chloro-6-((4-ethoxy-4-oxobutyl)(4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (5.5 g, 40%). 1H NMR (400 MHz, CDCl3): δ 7.12 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.66 (s, 2H), 4.16 (q, J=6.8 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 3.79 (s, 3H), 3.42 (t, J=7.6 Hz, 2H), 2.45 (s, 3H), 2.24 (t, J=6.8 Hz, 2H), 1.94 (quintet, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H). LCMS [M+H]: 482
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9](O)=[O:10])[C:7]([NH2:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:14]([O-])([O-])OC.C([O-])(=O)C.[NH4+:23].Cl>O.CO>[C:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:13]=[CH:14][NH:23][C:9]2=[O:10])([OH:3])=[O:2]
Reactant: [NH4+]
Reactant: COC([O-])[O-]
Reactant: Nc1ccc(C(=O)O)cc1C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.00 g (5.5 mmol) of 5-carboxyanthranilic acid, 2.30 g (22.0 mmol) of methyl orthoformate, 1.70 g (22.0 mmol) of ammonium acetate, and 4.0 mL of methanol. The reaction was carried out at 120° C. for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water and 10 mL of hydrochloric acid (1 mol/L) were added to the reaction mixture. The resulting aqueous mixture was stirred for 15 minutes and filtered to give 0.96 g (isolated yield: 84%, purity: 91% in terms of area percentage determined by high performance liquid chromatography) of 6-carboxyquinazolin-4-one as a yellow crystalline product.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][NH:23][N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(#N)C.O>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23]([CH2:26][CH2:27][OH:28])[N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4c[nH]nc34)ccn2)n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(CCO)nc34)ccn2)n1
Temperature: 120 °C
Yield: 8.7 %

Procedure:
N-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (21 mg, 0.066 mmol), 2-bromoethanol (8.19 mg, 0.066 mmol) and cesium carbonate (42.7 mg, 0.131 mmol) were combined in DMF (5 mL). The mixture was heated at 120° C. for 30 minutes, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-70% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to afford 2-(7-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)ethanol (2.1 mg, 8.79% yield). 2-(7-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanol containing fractions were concentrated and subsequently purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 5-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to afford the title compound as TFA salts.