Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[C:12]([C:14]1[C:15]([NH:22][CH2:23][CH3:24])=[N:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=1)=O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O.O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]([C:12]2[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[N:16][C:15]=3[N:22]([CH2:23][CH3:24])[C:6](=[O:7])[N:5]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCNc1nc(CC)ccc1C(=O)c1cccc(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc2c(-c3cccc(Cl)c3)nc(=O)n(CC)c2n1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Chlorosulfonyl isocyanate (0.8 ml, 9 mmol) was added to a tetrahydrofuran (50 ml) solution of 3-(3-chlorobenzoyl)-6-ethyl-2-ethylaminopyridine (2.6 g, 9 mmol) under ice-cooling, followed by stirring for 1 hour under ice-cooling. To the reaction solution were added water and saturated sodium bicarbonate aqueous solution in that order, followed by 30 minutes of stirring at room temperature. This was adjusted to pH 10 with 1 N sodium hydroxide aqueous solution and extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one (1.7 g, 60%) in the form of crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1.[Br:20]N1C(=O)CCC1=O>ClC1C=CC=CC=1.CO.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: Clc1ccccc1
Product: BrCc1cc2c3ccccc3ccc2c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of 6-methylchrysene (4,85 g, 20 mmol), N-bromosuccinimide (3.60 g, 20.2 mmol), and benzoyl peroxide (0.242 g, 1.0 mmol) in chlorobenzene (100 mL) was heated under nitrogen at 80° C. After 1 hour, NMR analysis indicated that the starting material had been consumed. The solution was cooled to 50° C. at which point a solid precipitate had formed. The mixture was diluted with methanol (100 mL) and further cooled to ambient temperature. The mixture was filtered and the solid washed with methanol to give 4.87 g (76% yield) of 6-bromomethylchrysene. 1H NMR (CDCl3) 5.17 (s, 2H), 7.25 (m, 4 H), 8.0 (t, J=8.7 Hz, 2 H), 8.31 (m, 1 H), 8.67 (d, J=9.0 Hz), 8.75 (d, J=9.0 Hz, 1 H), 8.81 (m, 2 H).
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8].[NH:14]([CH2:16]C(O)=O)[CH3:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]12[CH2:3][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:10][CH:11]1[N:14]([CH3:16])[CH2:15][CH2:13]2
Reactant: C=C(Cl)CN(CC=O)C(=O)OCC
Reactant: CNCC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2N(C)CCC2(Cl)C1

Procedure:
10.3 g (50 mmol) of ethyl N-(2-chloroallyl)-N-(2-oxoethyl)-carbamate are heated under reflux overnight with 4.5 g (50 mmol) of sarcosine in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4s3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of (S)-methyl 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (89 mg, 0.21 mmol) in methanol (25 mL) and chloroform (5 mL) was added sodium hydroxide (25.2 mg, 0.63 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (15 mL), adjusted pH to 5 with HCl (3 N) to give the precipitate, which was collected by filtration to afford (S)-2-(5-fluorobenzo[b]thiophen-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid (56 mg, 65%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.S([O-])(O)(=O)=O.I[CH2:17][CH3:18].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:17][CH3:18])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: N#CCc1cccc(Br)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(C#N)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
A solution of 3-bromophenylacetonitrile (8.12 g) in dichloromethane (150 mL) at room temperature was treated sequentially with tetrabutylammonuim hydrogen sulfate (14.1 g), iodoethane (10 mL), and 15% NaOH (35 mL), stirred for 4 hours, and separated. The aqueous phase was extracted with dichloromethane, and the combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% dichloromethane/hexanes to provide the desired product.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31]OS(C)(=O)=O)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31][N:43]4[CH2:44][CH2:45][CH:40]([OH:39])[CH2:41][CH2:42]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: CC(O)(COS(C)(=O)=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(CN1CCC(O)CC1)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Yield: 24.1 %

Procedure:
Methanesulfonic acid 2-[4-(4-benzyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-2-hydroxy-propyl ester (64 mg, 0.120 mmol) is combined with 4-hydroxy piperidine (61 mg, 0.600 mmol), diisoproylethylamine (63 μL, 0.360 mmol), and acetonitrile (1 mL). The mixture is heated to reflux for 16 h. Concentrate the crude mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (15.6 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 61.3 g of 2-(p-chlorophenoxy)ethanol, 73.5 ml of triethylamine and 900 ml of dichloromethane chilled at -10° C. is added dropwise a solution of 30.2 ml of methanesulfonyl chloride in 60 ml of dichloromethane. The mixture is stirred at -8° C. for 1 hour and worked up as described in Example 11 to give the product as a white solid. A dried sample of product melted at 75°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9]2[C:18](/[CH:19]=[CH:20]/[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:31])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.CC1C=CC(S(NN)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:18]([CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:31])[CH:15]=3)[N:10]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2/C=C/C(=O)NCC2CCCCC2)cc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2CCC(=O)NCC2CCCCC2)cc1
Temperature: 86 °C

Procedure:
To a stirred solution of (E)-3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)acrylamide (3.7 g, 7.3 mmol, prepared as in Example 2) in DME (100 mL) was added 4-methylbenzenesulfonohydrazide (13.6 g, 72.8 mmol). The mixture was brought to reflux at 86° C. and then via addition funnel was added dropwise a solution of sodium acetate (10.4 g, 127 mmol) in water (60 mL) over 1.5 h. Once the addition was complete, the reaction was refluxed for an additional 30 min, and then cooled to RT and concentrated to remove organic solvent. The crude material was dissolved in DCM (150 mL) and washed sequentially with 1N NaOH, 1N HCl, and then water. The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil, which upon purification via flash chromatography (5% EtOAc/DCM) afforded 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)propanamide. Step 2 In a sealed tube was combined 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)propanamide (0.16 g, 0.31 mmol), 2-chlorophenylboronic acid (0.074 g, 0.47 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.0044 g, 0.0063 mmol), potassium acetate (0.062 g, 0.63 mmol), ethanol (6.0 ml) and water (0.41 mL). The flask was sealed and heated in an oil bath at 85° C. for 16 h. The reaction mixture was cooled to RT, adsorbed onto silica and purified by flash chromatography (5% MeOH/DCM) to afford 3-(2-(4-methoxybenzylamino)-6-(2-chlorophenyl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide. Step 3 The product of step 2 was carried through the same procedure as described in Step 9, Example 2, to afford 3-(2-amino-6-(2-chlorophenyl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide. MS (ESI, pos. ion) m/z: 422 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([CH3:25])[CH:17]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=1[CH3:26].Cl.[NH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:12]([C:11]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:21])=[C:18]([CH3:25])[CH:17]=1)([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[C:27]([CH3:30])([CH3:28])[CH3:29])=[C:6]([CH3:26])[CH:7]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CS(=O)(=O)CCN
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)c(C)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoic acid, Example 1, (0.53 g, 1.29 mmol), 2-aminoethylmethylsulfone hydrochloride (0.21 g, 1.29 mmol), HOBt (0.19 g, 1.43 mmol), Et3N (0.72 mL, 5.19 mmol) and CH2Cl2 (10 mL) is added EDCI (0.249 g, 1.29 mmol) and stirred overnight. The reaction is diluted with CH2Cl2 (50 mL), washed with 1M HCl (2×30 mL), H2O (20 mL), satd NaHCO3 (2×20 mL), and brine (20 mL). The organic layer is MgSO4 dried, concentrated, and chromatographed (75% EtOAc/Hex) to give the title compound (0.51 g, 76%).
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[NH2:8][CH2:9][CH2:10][O:11][CH:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[N:16]([C:24](=[O:43])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[CH:27][C:26]=2[O:41][CH3:42])[CH2:15][CH2:14][CH2:13]1>C(O)C>[ClH:23].[NH:7]=[C:2]([NH:8][CH2:9][CH2:10][O:11][CH:12]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[N:16]([C:24](=[O:43])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[CH:27][C:26]=2[O:41][CH3:42])[CH2:15][CH2:14][CH2:13]1)[CH3:3]
Reactant: CCOC(C)=N
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Agent: Cl
Solvent: CCO
Product: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCNC(C)=N)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
0.129 g of ethyl acetoimidate hydrochloride was added to 15 ml of a suspension of 0.5 g of 5-(2-amino-ethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in ethanol with ice-cooling. The mixture was stirred overnight at room temperature. Then, 0.163 g of ethyl acetoimidate hydrochloride was further added. The mixture was stirred at 50° C. for 7 hours and then refluxed for 3 hours. After cooling, the reaction mixture was subjected to filtration to remove insolubles. The filtrate was concentrated. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=30/1) to obtain 0.2 g of 5-[2-(1-iminoethyl)aminoethoxy]-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)(=O)C>[C:10]([C:8]1[CH:7]=[N:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cncc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cncc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 3-nitro-5-((trimethylsilyl)ethynyl)pyridine (4.90 mmol) in MeOH (15 mL) was added K2CO3 (67 mg, 0.49 mmol). The mixture was stirred at rt for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and chromatographed (hexane/ethyl acetate) to afford the desired product (540 mg, 74% over two steps) as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 9.39-9.38 (m, 1H), 8.99-8.98 (m, 1H), 8.56-8.54 (m, 1H), 3.40 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:13]#[CH:14]>>[CH2:12]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:3])[CH2:17][CH2:16]1)[C:13]#[CH:14]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
4-(chloro)phenyl chloroformate (5.00 g, 26.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (5.50 g, 20.1 mmol) according to general procedure 1. Yield=4.83 g, 86%. m/z MH+=278.13. HPLC rt=13.0 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9].I[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([CH2:11][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:2]([NH2:1])[C:3]1=[O:9])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: NC1CCCCNC1=O
Reactant: CC(C)(C)OC(=O)CI
Product: CC(C)(C)OC(=O)CN1CCCCC(N)C1=O

Procedure:
3-Aminoperhydro-2-azepinone (R. Pellegata, et al., Synthesis, 1978, 614-616) was alkylated with t-butyl iodoacetate as described in Example 1, Step B, to afford 1-t-butoxycarbonylmethyl-3-aminoperhydro-2-azepinone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]=O)[N:11]=1.[CH3:30][NH:31][CH3:32].Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>ClCCCl>[CH3:30][N:31]([CH3:32])[CH2:28][CH2:27][CH2:26][N:12]1[C:13]2=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=[C:18]2[C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11]1
Reactant: Cc1cccc(C)c1Nc1nn(CCC=O)c2nc(Nc3ccccc3)ncc12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Nc1nn(CCCN(C)C)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 66 mg (0.2 mmol) of crude 3-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanal 36 (Example 4, Step A) and 28 mg (0.3 mmol) of dimethylamine•HCl in 7 mL of 1,2-dichloroethane was treated sequentially with 60 mg (95%, 0.3 mmol) of NaBH(OAc)3 and 75 μl (0.5 mmol) of triethylamine. The resulting brown slurry was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 44:6 grading to CH2Cl2:MeOH, 4:1) to give the title compound 38. 1H-NMR (CD3OD) δ 2.06-2.14 (m, 2H), 2.28 (s, 6H), 2.49 (s, 6H), 2.72 (t, J=7.3 Hz, 2H), 4.19 (t, J=6.3 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 7.12-7.19 (m, 3H), 7.31 (t, J=8.0 Hz, 2H), 7.75 (dd, J=8.6 Hz, 0.9 Hz, 2H), 8.27 (s, 1H). Mass Spectrum (ESI) m/e=416.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]4[CH:17]=[N:18][CH:19]=[C:15]4[CH:14]=[CH:13][C:12]=3[C:20](O)=[O:21])=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:17]=[N:18][CH:19]=2)[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:5][C:6]=1[F:23])=[O:21])=[CH2:25]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
To a mixture of 5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (400 mg, 1.29 mmol), O-(2-vinyloxyethyl)-hydroxylamine (265 mg, 2.57 mmol) and HOBt (225 mg, 1.67 mmol) in DMF (5 mL) was added EDCI hydrochloride (320 mg, 1.67 mmol), and DIPEA (0.290 mL, 1.67 mmol) before the reaction mixture was stirred at room temperature for 18 hours. The products were partitioned between ethyl acetate and saturated aqueous NaHCO3, the organic layer separated and washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-35% ethyl acetate in cylcohexane) to give the title compound (270 mg, 53%). LCMS (Method B): RT 2.79 [M+H]+ 397.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.CN.[NH2:9][C:10]1[C:11]([F:36])=[CH:12][C:13]([F:35])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23](F)[C:24]=3[CH3:26])[C:19](=[O:31])[C:18]([C:32]([OH:34])=[O:33])=[CH:17]2)[CH:15]=1>C(OCC)C>[NH2:9][C:10]1[C:11]([F:36])=[CH:12][C:13]([F:35])=[C:14]([N:16]2[C:25]3[C:20](=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([NH:1][CH3:2])[C:24]=3[CH3:26])[C:19](=[O:31])[C:18]([C:32]([OH:34])=[O:33])=[CH:17]2)[CH:15]=1
Reactant: c1ccncc1
Reactant: Cc1c(F)c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: CN
Solvent: CCOCC
Product: CNc1c([N+](=O)[O-])cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
Pyridine (500 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-8-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (220 mg), and the mixture was stirred for 3 hours at 40° C. and for 2 days at room temperature. Diethyl ether was added to the reaction mixture, followed by stirring. A supernatant liquid was removed, and acetic acid (3 drops) was added to the residue, followed by stirring. Solids deposited were recrystallized from ethanol and N,N-dimethylformamide to obtain the title compound (190 mg) as a reddish brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[K+].[C:37]([O:43][CH2:44]Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C)C=O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:9]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 81.6 %

Procedure:
3-Methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylic acid (69.6 g., 0.2 mole) was dissolved in 300 ml. of dimethylformamide and reacted in sequence with triethylamine (20.2 g., 0.2 mole), potassium bicarbonate (40 g., 0.4 mole) and chloromethyl pivalate (33 g., 0.22 mole) according to procedures detailed in Preparation B 1. To isolate the product, the reaction mixture was diluted with 3 l. of ether, and the organic solution washed, dried and evaporated to dryness, as detailed in Preparation 1, affording pivaloyloxymethyl 3-methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylate [75.5 g., 82%; ir (CH2Cl2) 1776, 1750, 1685 cm-1 ].
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=[O:4].[CH:8]([C:11]1[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][C:16]=1[O:17][CH3:18])([CH3:10])[CH3:9].P([O-])([O-])(O)=O.[Na+].[Na+]>C1C=CC=CC=1>[OH:4][CH:3]=[C:13]1[C:12](=[O:19])[C:11]([CH:8]([CH3:10])[CH3:9])=[C:16]([O:17][CH3:18])[CH2:15][CH2:14]1
Reactant: COC1=C(C(C)C)C(=O)CCC1
Reactant: CCOC=O
Agent: O=P([O-])([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC1=C(C(C)C)C(=O)C(=CO)CC1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a suspension of sodium hydride (3.6 g, 60% suspension, 90 mmol) in benzene (100 mL), a mixture of ethyl formate (12.5 g) and 2-isopropyl-3-methoxy-cyclohex-2-enone (5g, 29.7 mmol) in benzene was added dropwise at 5° C. The reaction mixture was stirred at ice temperature for 1 hour, and at room temperature for 18 hours. The reaction mixture was cooled in an ice bath, and 10% sodium hydrogen phosphate solution (200 mL) was added dropwise. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as a thick viscous liquid (3.5 g, 60%). 1H NMR (CDCl3): δ 1.15 (d, 6H, 2×CH3), 2.35–2.6 (m, 4H, 2×CH2), 3.15 (m, 1H, CH), 3.8 (s, 3H, OCH3), 7.17 (d, 1H, ═CHOH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:18](O)=O>>[CH3:16][N:15]([CH2:14][CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:18]1)[CH3:17]
Reactant: CN(C)CCNc1c(N)cnc2ccccc12
Reactant: O=CO
Product: CN(C)CCn1cnc2cnc3ccccc3c21

Procedure:
Using the method of Example 137, 3-amino-4-[2-(N,N-dimethylamino)ethylamino]quinoline (from Example 46) was reacted with formic acid to provide 1-[2-(N,N-dimethylamino)ethyl]-1H-imidazo[4,5-c]quinoline. The product was dissolved in ethanol and hydrogen chloride was bubbled into the solution. The precipitate was separated by filtration, washed with ethanol and recrystallized from ethanol. The product was 1-[2-(N,N-dimethylamino)ethyl]-1H-imidazo[4,5-c]quinoline trihydrochloride hydrate, m.p. >250° C. Analysis: Calculated for C14H16N4.3 HCl.H2O: %C, 45.8; %H, 5.5; %N, 15.3: Found: %C, 46.0; %H, 5.2; %N, 15.5.