Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:16]1[CH2:15][N:14]([C:11]2[S:12][CH:13]=[C:9]([C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:8])[N:10]=2)[CH2:17]1)(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of 1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (680 mg, 1.96 mmol) (obtained as described in Reference Example 11(3)) in dimethylformamide (20 ml) was added potassium thioacetate (671 mg, 5.87 mmol) at room temperature, and then the reaction mixture was stirred in an oil bath (80° C.) for 18 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:3)→ethyl acetate as the eluant to afford 3-acetylthio-1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidine (411 mg, yield 64%) as a pale brown solid.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[S:14][C:13]([CH2:15]O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.Cl.[C-:22]#[N:23].[Na+].N>CS(C)=O>[N:1]1([CH:6]([C:10]2[S:14][C:13]([CH2:15][C:22]#[N:23])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(CO)s1)n1ccnc1
Reactant: [C-]#N
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Product: CCCC(c1ccc(CC#N)s1)n1ccnc1
Reaction time: 20 h

Procedure:
0.2 g of the alcohol of example 8 is converted, with thionyl chloride (2 hours at room temperature, concentration by evaporation, redistillation three times with toluene) into the hydrochloride of the chloromethyl compound, which is dissolved in 2 ml of dimethyl sulfoxide and is mixed with 0.2 g of sodium cyanide. After stirring for 20 hours, it is added to dilute ammonia solution, extracted with ethyl acetate and the ethyl acetate extract is dried and concentrated by evaporation. After distillation on a bulb tube, the title compound is obtained as oil. Boiling point: 210°-230° C./0.03 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[N:16][OH:17])=[CH:11][CH:10]=2)[CH2:6]1)=[O:4].ClN1C(=O)CCC1=O.C(=O)([O-])O.[K+].[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[CH:35]=[C:34]([Cl:44])[C:33]=1[Cl:45]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:39][C:38]([C:36]4[CH:35]=[C:34]([Cl:44])[C:33]([Cl:45])=[C:32]([Cl:31])[CH:37]=4)([C:40]([F:43])([F:42])[F:41])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(c2ccc(C=NO)cc2)C1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a stirred solution of 1-[4-(hydroxyimino-methyl)-phenyl]-azetidine-3-carboxylic acid methyl ester (Preparation 10, 2.36 g, 10.08 mmol) in DMF (25 mL) was added N-chloro succinimide (1.48 g, 11.09 mmol) at 0° C. Resulting reaction mixture was stirred at 0° C. for 1 hour and then at 10° C. for 1 hour. After complete consumption of starting material to chloro intermediate (red colored reaction mixture) potassium hydrogen carbonate (1.51 g, 15.12 mmol, 1.5 eq.) was added followed by of 1,2,3-trichloro-5-(1-trifluoromethyl-vinyl)benzene (1.21 g, 12.10 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 4 hours under nitrogen atmosphere. After consumption of chloro intermediate, reaction mixture was quenched with water (200 mL) and extracted with EtOAc (2×200 mL). Combined organic layer was washed with water (2×400 mL), brine (2×200 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford brown colored semi solid (2.5 g, crude). Crude compound was purified by column chromatography (silica gel, 100-200 mesh). Compound was eluted using 25% ethyl acetate in hexane to afford off white solid (1.91 g, 33%). 1H NMR (400 MHz, CDCl3): 3.58-3.63 (m, 2H), 3.75 (s, 3H), 4.03 (d, 1H, J=17.04 Hz), 4.07-4.15 (m, 4H), 6.39-6.42 (m, 2H), 7.46-7.49 (m, 2H), 7.63 (s, 2H); LC-MS (M+H): =506.90.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[N:11][CH:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2ccncc12
Reactant: Nc1cccc(Br)c1
Product: Brc1cccc(Nc2ncnc3ccncc23)c1
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 4-methylthiopyrido[4,3-d]pyrimidine (171 mg, 0.96 mmol), (see previous experimental) and 3-bromoaniline (1 mL) is heated to 100° C. for 2 h. A solid precipitates on cooling and is collected by vacuum filtration and then recrystallized from EtOH to yield 4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (30 mg, 10%). 1H NMR (DMSO) δ 10.33 (1H, s), 9.86 (1H, s), 8.84 (1H, d, J=5.8 Hz), 8.79 (1H, s), 8.22 (1H, s), 7.89 (1H, d, J=7.2 Hz), 7.69 (1H, d, J=5.8 Hz), 7.40 (2H, dt, Jd=8.0 Hz, Jt=1.5 Hz).
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:15]=1>>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:16]1[N:15]=[C:14]([NH:11][S:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:12])[CH2:7][CH2:6]2)(=[O:9])=[O:10])[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1
Reactant: NS(=O)(=O)N1CCS(=O)(=O)CC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: COc1cc(NS(=O)(=O)N2CCS(=O)(=O)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from 1,1-dioxothiomorpholine-4-sulfonamide (0.31 g, McManus, J. M. et al, J. Med. Chem (1965) 8 766-776) and 4-chloro-2-[[(2,3-difluorophenyl) methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (1:1) as eluent. Yield: 0.48 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 54 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.22 g, 0.014 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into three portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 2.6 g (54% yield) of an oily glass. The glass was dissolved in hot isopropyl ether (with a little isopropyl alcohol added), filtered while hot, and cooled to room temperature with stirring, causing a solid to precipitate. The mixture was cooled in the freezer, and the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature to give 1.60 g of title compound, mp. 110°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.064 mmol) was dissolved in anhydrous EtOH (0.6 mL) followed by addition of 2 M of sodium hydroxide in water (60 μL). Reaction was stirred at 50° C. for 4 hrs. Consumption of starting material was monitored by TLC. The sample was quenched with acetic acid, diluted with MeOH and purified by preparative LCMS. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash silica column chromatography to yield the desired product (16 mg, 87%). 11-1 NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 9.02 (s, 1H), 7.18 (dd, J=9.1, 9.1 Hz, 1H), 6.97 (dd, J=6.6, 2.7 Hz, 1H), 6.69 (m, 1H), 5.68 (t, J=6.2 Hz, 1H) 4.72 (d, J=5.8 Hz, 2H); MF=C10H8ClFN4O3; LCMS calculated for C10H9ClFN4O3(M+H)+: m/z=287.035.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([Br:11])[CH2:9][CH2:8][C:7]2[N:6]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.[Cl:21][CH2:22][CH:23](O)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:21][CH2:22][CH:23]1[CH2:24][O:25][C:2]2([CH:10]([Br:11])[CH2:9][CH2:8][C:7]3[N:6]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]2=3)[O:1]1
Reactant: O=C1c2ccn(S(=O)(=O)c3ccccc3)c2CCC1Br
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c1CCC(Br)C21OCC(CCl)O1
Yield: 97 %

Procedure:
In a three necked flask equipped with a thermometer, a stirrer and a reflux condenser having Widmer-type water trap filled with Molecular Sieves are placed 4-oxo-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole (100 parts), 3-chloro-1,2-propanediol (311 parts), p-toluene-sulfonic acid monohydrate (3 parts) and roluene (4500 parts), and the mixture is refluxed for 7 hours 20 minutes while drying the refluxing azeotropic mixture. After cooling, the reaction mixtue is adjusted to pH 9 with 2.5N aqueous sodium hydroxide with stirring, and the formed toluene layer is separated. The water layer is washed with benzene (200 parts). Toluene layer and benzene washing are combined, washed twice with water (500 parts) and dried over anhydrous sodium sulfate (500 parts). The drying agent is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue (143 parts) is dissolved in benzene (300 parts), stirred with active charcoal (50 parts) for 30 minutes and filtered through a filter-bed of siliceous earth. The filtrate is concentrated under reduced pressure, and stirring of resulted residue with a small amount of ether and hexane affords amorphous powder. This is collected by filtration, washed with a mixture of ether and hexane, and dried to give 4'-chloromethyl-5-bromo-1-benzenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]-dioxolane diastereomer mixture (122 parts) in 97% yield.
Reaction SMILES: Cl[C:2](=[O:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[O:18].C([O-])(=O)C.[Na+]>ClCCl.O>[O:14]=[C:2]([NH:15][CH2:16][C:17](=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(=O)Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnn(CC(=O)NCC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
The compound (3.2 g) obtained in Example 115c and 2-amino-1-[3-(trifluoromethyl)phenyl]ethanone (2.88 g) were dissolved in dichloromethane (120 mL) and water (40 ml), and an aqueous solution (40 mL) of sodium acetate (2.46 g) was added dropwise under cooling in an ice bath. The reaction mixture was stirred at room temperature overnight, and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether-ethyl acetate) to give the title compound (0.92 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[N:21][CH:20]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: Cc1ncc(C(CN)CC2CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2c(Cl)cccc2Cl)CC2CC2)cn1

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=364.1, tR (minutes, Method G)=2.43
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31]([O-])=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C([O-])c1ncoc1-c1ccncc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccncc3)cn2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-pyridin-4-yl-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 02: tR=0.70 min; [M+H]+=378.15.
Reaction SMILES: [N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH3:33][N:34]1[C:38]([CH:39]=[O:40])=[CH:37][N:36]=[C:35]1[CH3:41]>C1COCC1>[N:1]1([C:5]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:13]([Cl:26])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH:39]([C:38]4[N:34]([CH3:33])[C:35]([CH3:41])=[N:36][CH:37]=4)[OH:40])[CH:11]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(Cc2c(N3CCC3)nc3ccc(Br)cc3c2Cl)cc1
Reactant: Cc1ncc(C=O)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc(C(O)c2ccc3nc(N4CCC4)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)n1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-(Azetidin-1-yl)-6-bromo-4-chloro-3-(4-(trifluoromethyl)benzyl)quinoline (1.00 g, 2.19 mmol, Intermediate 69: step a) was dissolved in THF (20 mL) in a dry round bottom flask under an N2 atmosphere, then cooled to −78° C. in dry ice acetone bath. n-BuLi (1.6 M in hexanes, 1.74 mL, 2.79 mmol) was then added dropwise via syringe over approximately 5 minutes. The contents were stirred at −78° C. for approximately 10 minutes, then a solution of 1,2-dimethyl-1H-imidazole-5-carbaldehyde (0.30 g, 2.4 mmol) in THF (20 mL) was added via cannula and the resulting mixture stirred for 10 minutes at −78° C. The dry ice bath was then removed and replaced with an ice water bath and the mixture stirred at 0° C. for approximately one hour. The reaction was then quenched with a saturated, aqueous NH4Cl solution, then transferred to a separatory funnel with EtOAc. The organic phase was extracted with a saturated, aqueous NH4Cl solution and deionized water, then separated and dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM) to provide the title compound.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:24])(=[NH:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:21][CH:20]([C:19]1[N:23]=[CH:4][C:5]2[CH2:6][C:7](=[O:17])[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:24]=1)[CH3:22]
Reactant: CC(C)C(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Agent: Cl
Product: CC(C)c1ncc2c(n1)-c1ccccc1NC(=O)C2
Yield: 87 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and isobutyramidine hydrochloride. Yield: 87%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[CH:17][N:16]=[C:15]([NH2:21])[C:14]=2[N:13]=[C:12]1[CH2:22][O:23][CH2:24][CH3:25].C(N(CC)CC)C.C(Cl)(Cl)Cl>[OH-].[Na+]>[NH2:21][C:15]1[C:14]2[N:13]=[C:12]([CH2:22][O:23][CH2:24][CH3:25])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]=2[C:18]([CH3:20])=[CH:17][N:16]=1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (4 eq) was added dropwise to a mixture of 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine (2.25 g, 8.11 mmol), triethylamine (10.2 mL, 73.0 mmol) and chloroform (225 mL). The solvent was removed under reduced pressure to provide an oil. The oil was dissolved in 10% sodium hydroxide (200 mL) then extracted with chloroform (3×300 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure to provide a clear oil. The oil was purified by column chromatography (silica gel eluting with 90/10 dichloromethane/methanol) to provide a white solid. This material was dried overnight under vacuum at 80° C. to provide 0.71 g of N-{4-[4-amino-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide as a white solid, m.p. 173-175° C. Analysis: Calculated for C15H25N5O3S: % C, 50.69; % H, 7.09; % N, 19.70; Found: % C, 50.51; % H, 6.91; % N, 19.49.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]3[O:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=3[CH:41]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:34]4[O:39][CH2:38][C:37](=[O:40])[NH:36][C:35]=4[CH:41]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)CO3)OC1(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)NC(=O)CO5)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+=471.0/473.0.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([NH:24][CH3:25])=[O:23]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:20][C@@H:21]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([NH:24][CH3:25])=[O:23])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=404.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([CH2:7][CH:8]([CH3:12])[C:9](O)=[O:10])=O.O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH:8]([CH3:12])[C:9](=[O:10])[NH:17][N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC(CC(=O)c1cccc(Cl)c1)C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1CC(c2cccc(Cl)c2)=NNC1=O

Procedure:
A mixture of 7.11 g. of 3-(m-chlorobenzoyl)-2-methylpropionic acid, 50 ml. of ethanol and 3.0 ml. of hydrazine hydrate is refluxed for 2 hrs. Cooling and filtering gives crystals, (m.p. 150°-151° C.) which are recrystallized from ethanol to give 5.72 g. of crystals, m.p. 152°-153°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[C:15](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:29])[CH2:16][C:17](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:18].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:15]([OH:29])=[CH:16][C:17](=[O:18])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nnc(SCc2ccccc2)s1
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CCCCCC
Solvent: Clc1ccccc1
Product: O=c1cc(O)nc2sc(SCc3ccccc3)nn12
Reaction time: 0.33 h
Yield: 97.9 %

Procedure:
A mixture of 44.7 g of 2-amino-5-benzylthio-1,3,4-thiadiazole, 98.1 g of bis(2,4,6-trichlorophenyl) malonate and 140 ml of chlorobenzene was heated to 130°-140° C. and stirred for 20 minutes. After cooling, hexane was added to the mixture, and the formed precipitate was separated by filtration. The solid was washed with hexane and thus 57.1 g of 2-benzylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 98%.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[O:6][CH2:5][CH2:4][O:3]1.O.NN>C(O)C>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(CCCCCCN2C(=O)c3ccccc3C2=O)OCCO1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1(CCCCCCN)OCCO1
Yield: 48.3 %

Procedure:
A mixture of 125.25 g (0.395 mole) of N-[6-(2-methyl-1,3-dioxolan-2-yl)hexyl]phthalimide, 23 ml of 85% hydrazine hydrate, and 370 ml of 95% ethanol was refluxed for four hours, cooled, filtered and stripped. The residue was mixed with 500 ml of water, basified with 2 N NaOH solution and extracted with methylene chloride. The organic layer was separated, dried over anhydrous potassium carbonate, filtered, and stripped to an orange oil. This material was distilled to give 35.70 g (64%) of clear oil bp 80°-83° (0.100 mm).