Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cnc3ccccc3c2)CC1
Reaction time: 16 h
Yield: 56 %

Procedure:
A mixture of quinolin-3-ylamine (3.62 g, 25.09 mmol, 1.0 equiv, commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 25.09 mmol, 1.0 equiv; commercially available) in conc. acetic acid (1.44 mL, 1.51 g, 25.09 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (6.38 g, 30.11 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:1→9:1). Trituration from heptane/ethyl acetate provided 4.60 g (56%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.36-1.46 (m, 2H), 1.49 (s, 9H), 2.12 (d, J=10.5 Hz, 2H), 3.00 (t, J=11.9 Hz, 2H), 3.47-3.64 (m, 1H), 3.89 (d, J=7.7 Hz, 1H), 4.10 (br s, 2H), 7.03 (d, J=2.7 Hz, 1H), 7.37-7.47 (m, 2H), 7.59-7.64 (m, 1H), 7.89-7.98 (m, 1H), 8.42 (d, J=2.7 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:38]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1)(=[O:40])[CH3:39]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCN)cc(OC)c1C
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCNC(C)=O)cc(OC)c1C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
To a solution of compound 44a (21 mg, 0.05 mmol) and pyridine (0.008 mL, 0.1 mmol) in dichloromethane (1 mL) was added acetyl chloride (0.004 mL, 0.055 mmol). The reaction mixture was stirred for 1.5 h, and additional acetyl chloride (0.004 mL) was added. After an additional 5 min, the reaction was quenched by addition of water and concentrated. The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to afford compound 45a (8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[N:13]=1>>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([S:17]([NH:4][C:3]2[C:5]([Cl:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=2[Cl:1])(=[O:19])=[O:18])[N:13]=1
Reactant: Nc1nc(S(=O)(=O)Cl)n[nH]1
Agent: Cc1ccc(Cl)c(N)c1Cl
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
4.4 g (0.025 mol) of 2,6-dichloro-3-methylaniline are heated to 110° C., 1.8 g (0.01 mol) of 5-amino-3-chlorosulfonyl-1,2,4-triazole are added under argon and the suspension is stirred for 90 minutes at this temperature. After work-up similar to example 1, 3.1 g (99.4% purity) of 2,6-dichloro-3-methylaniline and 1.81 g (95.3% purity) of 5-amino-N-(2,6-dichloro-3-methylphenyl)-1,2,4-triazole-3-sulfonamide are obtained. The theoretical yield is found to be 56.2%, and based on unrecovered aniline the yield is 76.1% of the theory.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl.O.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([NH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)N1CCOCC1
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3c(c2n1NCCCNC(=O)N1CCOCC1)CCCC3
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.2 %

Procedure:
A solution of N-(3-{[4-amino-2-(ethoxymethyl)-1 H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)morpholine-4-carboxamide (0.120 g, 0.281 mmol) in 12 mL of TFA was treated with platinum (IV) oxide (0.064 g, 0.28 mmol). The mixture was placed under an atmosphere of hydrogen (3.8×105 Pa) and shaken at ambient temperature. After 17 h, the reaction mixture was diluted with 15 mL of 4:1 CHCl3:MeOH and then filtered through a pad of CELITE filter agent and rinsed through with portions of 4:1 CHCl3:MeOH (1% TFA). The clear colorless filtrate was concentrated under reduced pressure to yield a white solid. The material was suspended in 15 mL of H2O and treated with 10% NaOH solution until the pH of the liquid was 13. A white solid was collected by vacuum filtration. The solid was purified by chromatography (SiO2, 25–30% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a white foam. The foam was triturated with Et2O and filtered to yield N-(3-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)morpholine-4-carboxamide (0.050 g) as a white solid. mp 152–154° C.; 1H NMR (300 MHz, DMSO-d6) δ 6.52 (t, J=5.4 Hz, 1H), 6.31 (t, J=5.9 Hz, 1H), 5.83 (s, 2H), 4.61 (s, 2H), 3.58–3.50 (m, 6H), 3.24–3.21 (m, 4H), 3.12 (q, J=6.7 Hz, 2H), 3.06–3.00 (m, 4H), 2.67–2.64 (m, 2H), 1.78–1.72 (m, 4H), 1.66–1.61 (m, 2H), 1.14 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 157.6, 149.4, 148.9, 146.5, 137.1, 105.0, 65.8, 65.2, 62.9, 51.3, 43.7, 37.8, 32.0, 28.1, 22.8, 22.5, 22.0, 14.9; MS (APCI) m/z 432 (M+H)+; Anal. Calcd for C21H33N7O3•5H2O: C, 57.25; H, 7.78; N, 22.26; Found: C, 57.30; H, 7.82; N, 22.29.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[CH3:12][O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([O:13][CH3:12])=[O:23])=[CH:20][CH:19]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(Cn2cnc3c(Cl)nc(N)nc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-amino-6-chloropurine (5 g, 0.029 mol), 4-(bromomethyl)benzoic acid methyl ester (6.7 g, 0.029 mol), and potassium carbonate (4.0 g, 0.029 mol) in dry DMF (75 ml) is stirred at room temperature for three days. The reaction mixture is filtered and the filtrate is evaporated to near dryness under vacuum. Water is added and the precipitate is collected by filtration to give a mixture of 7- and 9-substituted products (10.5 g). A sample of pure 9-isomer, i.e., 2-amino-9-[(4-carbomethoxyphenyl)methyl)-6-chloropurine, (mp=150°-155° C. softens, 183°-185° C. melts) is prepared by chromatography on silica gel with 5% methanol/chloroform as the eluting solvent to separate it from the slower moving 7-isomer.
Reaction SMILES: Br[C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:5][S:4][CH:3]=1.CC[O:17][CH2:18]C.C1C[O:23]CC1>>[Cl:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]1[C:2]([C:18]([OH:17])=[O:23])=[CH:3][S:4][CH:5]=1
Reactant: Clc1cccc(Cc2cscc2Br)c1
Reactant: CCOCC
Reactant: C1CCOC1
Product: O=C(O)c1cscc1Cc1cccc(Cl)c1

Procedure:
3-Bromo-4-(3-chlorobenzyl)thiophene from Example 3, Step 2 (6.22 g, 21.6 mmol) was reacted under conditions similar to Example 1, Step 6 (Et2O was used as a solvent instead of THF), to afford the desired product as an off-white solid that was used directly without further purification.
Reaction SMILES: C(OCC)(=O)C.[CH3:7][C@H:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)C>C(Cl)(Cl)Cl>[CH3:7][CH:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mother liquors from above were acidifed with 167 ml. 1N hydrochloric acid, extracted with 5×125 ml. ethyl acetate, the extracts combined, washed with brine, dried (MgSO4) and the solvent evaporated to obtain 49 g. of residue. This was dissolved in 350 ml. warm ethyl acetate, 22.4 g. l-(-)-alpha-methylbenzylamine added and the solution cooled to room temperature. Ethyl ether, 350 ml. was added and the mixture refrigerated overnight. The precipitated solid was collected by filtration, washed with cold ether and dried in vacuo to obtain 44.0 g. of salt. This was dissolved in 880 ml. ethyl acetate and set aside at room temperature for six hours. Filtration gave 12.4 g., M.P. 139°-140° C. After standing overnight, the mother liquor afforded a second crop, 11.66 g., M.P. 139°-140° C. The optical rotation (in chloroform) for the first crop was [alpha]D -30.9°, and [alpha]D -26.6° for the second crop.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])=[O:9])(=[O:3])[CH3:2].[Cl-].[C:27](OC1C(=CC=CC=1)C(O)=O)(=[O:29])[CH3:28].C(O)COCCOCCOCCO>C(N(CC)CC)C>[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:28][CH2:27][OH:29])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: [Cl-]
Solvent: OCCOCCOCCOCCO
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)OCCOCCOCCOCCO)c(O)c1C(C)=O

Procedure:
The compound (II) was prepared according to the procedure described for the synthesis of triethylenglycol bis-acetylsalicylate (XIX), starting from 2 g of the chloride of acetylsalicylic acid, 0.93 g of tetraethylenglycol and 1.5 ml of trietylamine. The product was purified on silica gel chromatography utilizing an eluent mix constituted by methylene chloride/ethyl acetate 1:1 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and 0.6 g of tetraethylenglycol bis-acetylsalicylate (II) were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])[CH2:15][CH2:14]1.O>CN(C=O)C>[O:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([NH:23][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:18]1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: Nc1cccc(CN2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnn2ccc(Nc3cccc(CN4CCOCC4)c3)nc12
Temperature: 140 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (30 mg, 0.166 mmol) in DMF was added 3-(morpholinomethyl)aniline (233 mg, 1.213 mmol). The mixture was heated in microwave for 40 minutes at 140° C. Water was added and the solid formed was isolated by filtration to yield 5-(3-(morpholinomethyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=338)
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C(Cl)(=O)C([Cl:25])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:25])=[O:9])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (1.37 g, 4.69 mmol, 1.00 equiv) in dichloromethane (17 mL) was added 2 drops of N,N-dimethylformamide followed by the addition of oxalyl dichloride (3.63 g, 28.14 mmol, 6.00 equiv). The resulting solution was stirred for 1 h at 50° C. in an oil bath then concentrated under vacuum to afford 1.41 g (87%) of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride as a gray-yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[C:7]([O:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)(=[O:9])[NH2:8]>CO>[ClH:1].[C:7]([O:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:12]1)(=[O:9])[NH2:8]
Reactant: NC(=O)O[C@@H]1CCNC1
Reactant: N#CCCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CCl)N1CC[C@@H](OC(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.646 ml of chloroacetonitrile was added to a solution of 23 mg of metallic sodium in 8 ml of absolute methanol, the mixture was stirred for about 60 minutes at room temperature, 1.70 g of (3R)-3-carbamoyloxypyrrolidine hydrochloride were then added, and the mixture was stirred for a further 3 hours. After completion of the reaction, a small amount of insoluble material was filtered off and the solvent was stripped off from the filtrate. Ether was added to the residue, and the precipitated crystals were collected by filtration and washed with ether, giving 2.20 g of 2-[(3R)-3-carbamoyloxypyrrolidin-1-yl]-2-iminoethylchloride hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][OH:19])([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH:18]=[O:19])([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12]1
Reactant: OCCC1(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCC1(CC=O)CC1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
7.0 ml (79.9 mmol) of oxalyl chloride were dissolved in 45 ml of abs. dichloromethane, the mixture was cooled to −50° C. and a solution of 10.9 ml (163.6 mmol) of DMSO in 45 ml of abs. dichloromethane was added dropwise. After the end of the addition, the mixture was stirred at −50° C. for another 10 min, and 4.0 g (30.7 mmol) of 2,2′-cyclopropane-1,1-diyldiethanol, dissolved in 45 ml of abs. dichloromethane, were then added slowly. The resulting suspension was stirred at −50° C. for 10 min and then cooled to −78° C., and a solution of 44.5 ml (320 mmol) of triethylamine in 75 ml of abs. dichloromethane was added dropwise. After the end of the addition, the reaction mixture was stirred at −78° C. for 30 min and then slowly warmed to RT and subsequently washed with saturated aqueous sodium bisulphate solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. This gave 5.10 g of the target product as an orange oil (crude product of a purity of about 70%, about 92% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9](OC)S[C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:13]([O:18]C)(OC)(=O)=O.[CH:20](Cl)(Cl)Cl>>[Cl:1][C:2]1[C:7]2[N:8]([CH3:9])[CH2:20][S:13](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc2c(Cl)cccc2s1
Reactant: ClC(Cl)Cl
Reactant: COS(=O)(=O)OC
Product: CN1CS(=O)c2cccc(Cl)c21
Temperature: 150 °C
Yield: 99.7 %

Procedure:
A mixture of 4-chloro-2-methoxybenzothiazole (3.00 g, 0.015 mole) and dimethyl sulfate (95 mg, 7.5×10-4 mole) was heated at 150° C. for 3 hours with stirring. After cooling, the reaction mass was dissolved in chloroform, and the chloroform layer was washed with an aqueous solution saturated with sodium carbonate and then with water. The solvent was removed under reduced pressure to obtain 2.99 g of 4-chloro-N-methylbenzothiazolone as white crystals. Yield 99.7%, purity 99.0%, m.p. 130°-132° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1)=[O:6])[CH:2]=[CH2:3].[I:39][CH2:40][C:41]([NH2:43])=[O:42]>CC(C)=O>[I-:39].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][CH2+:33]1[N:37]([CH2:40][C:41](=[O:42])[NH2:43])[CH:36]=[CH:35][N:34]1[CH3:38])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCc3nccn3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: NC(=O)CI
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[CH2+]3N(C)C=CN3CC(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(1-methylimidazol-2-yl)ethyl}-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.04 g) in acetone (5 ml) was added iodoacetamide (1.06 g) with stirring at ambient temperature and then allowed to stand overnight. The reaction mixture was evaporated in vacuo and dried in vacuo for 1 hour to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(3-carbamoylmethyl-1-methyl-2-imidazolio) ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (1.39 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=2)=[CH:4][CH:3]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28].O>O1CCCC1>[CH2:20]([NH:19][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[NH:30][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=2)[N:14]=[CH:13][C:12]=1[CH2:15][C:16]([NH2:18])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)N=C=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N)cc2)cc1NCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1ccc(Nc2cc(NCc3ccccc3)c(CC(N)=O)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.5 %

Procedure:
10 mg of 6-[(4-aminophenyl)amino]-4-(benzylamino) pyridine-3-carboxyamide (the compound of Example 65) was dissolved in 0.5 mL of tetrahydrofuran, and, under ice cooling, 7.6 mg of isopropyl isocyanate was added, and stirred at room temperature for 24 hours. To the reaction mixture, water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was washed with methanol-ether to obtain 15 mg (80%) of the title compound as a light pink crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1)[CH3:2]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCn1cnc2ccccc21
Yield: 90.9 %

Procedure:
Ethyl-3-bromopropanoate (1.29 g, 7.1 mmol), benzimidazole (0.70 g, 5.9 mmol), and potassium carbonate (2.44 g, 17.7 mmol) were combined in anhydrous acetonitrile (60 mL) and heated to reflux for 3 days. Aqueous work-up gave ethyl-3-(benzimidazol-1-yl)propanoate (1.17 g, 91%). 1H NMR (CDCl3) δ 2.02 (s, 3H), 2.26 (m, 2H), 4.10 (t, 2H, J=6 Hz), 4.30 (t, 2H, J=6 Hz), 7.28 (br, 2H), 7.33 (br, 1H), 7.84 (br, 1H), 7.94 (br, 1H), 7.60 (br, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(N(CC)CC)C>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCC4)c23)C1
Temperature: 160 °C
Reaction time: 18 h
Yield: 30.4 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide (188 mg, 0.602 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (362 mg, 1.81 mmol), and triethylamine (168 μL, 1.20 mmol) in n-BuOH (5 mL) was stirred at 160° C. in a sealed tube for 18 hours. The mixture was allowed to cool to room temperature, and was then diluted with EtOAc (100 mL) and washed with brine (2×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The liquid residue was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 12-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(cyclobutanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (90 mg, 30% yield) as a solid. This material was dissolved in neat TFA (3 mL) and stirred at room temperature for 30 minutes. The mixture was then concentrated in vacuo, and the oily residue was dissolved in a few drops of CH2Cl2 and treated with 2M HCl in ether. The solid formed was crystallized from MeOH and CH3CN to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide hydrochloride (65 mg, 79% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.81 (s, 1H), 9.19 (s, 1H), 8.29 (br s, 3H), 8.23 (s, 1H), 7.59 (s, 1H), 3.46-3.37 (m, 2H), 3.35-3.26 (m, 3H), 3.08-3.03 (m, 1H), 2.34-2.24 (m, 2H), 2.18-2.11 (m, 3H), 2.01-1.94 (m, 1H), 1.86-1.80 (m, 2H), 1.70-1.60 (m, 1H), 1.50-1.44 (m, 1H); LCMS (APCI+) m/z 392, 394 (M+H)+, Retention time=2.28 minutes (Method 2).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[CH2:20][N:21](C(C)C)[CH:22](C)C.CNC.C1COCC1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([N:21]([CH3:22])[CH3:20])=[O:18])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 479.4 %

Procedure:
To a solution of (2S,4S)-1-Boc-4-azidopyrrolidine-2-carboxylic acid (9.5 g, 35 mmol) prepared in Step A in DMF (30□) was added dropwise DIPEA (1.15□, 6.70 mmol), and added dropwise 2M dimethylamine-THF solution (26.3 ml, 52.5 mmol), HOBT (7 g, 52.5 mmol) and EDC (10.2 g, 52.5 mmol) in order. The reaction mixture was stirred at rt for 12 h, and concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NaHCO3 aqueous solution, water and 1N HCl. The organic solution was dried over MgSO4, concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (9.1 g, 93%).