Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([NH2:14])[CH3:13]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:12][CH3:13])=[O:9]
Reactant: CCN
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
2.0 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphine (5.2 mmol) were added to 1.0 g of 5,6-dichloronicotinic acid (5.2 mmol) dissolved in 2.4 mL of tetrahydrofuran and 2.5 mL of dimethylformamide, and stirred at room temperature for 10 minutes. 2.6 mL of ethylamine in 2.0 M tetrahydrofuran solution (5.2 mmol) was added thereto, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, concentrated under reduced pressure to be dissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.8 g of 5,6-dichloro-N-ethyl-nicotinamide (yield 70%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[CH:9][CH:10]=2)[N:5]=1>C(O)C.O1CCCC1>[Cl:3][C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[C:6](=[CH:7][C:8]([CH3:16])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2cc(C=O)c(Cl)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc2cc(CO)c(Cl)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a stirred solution of 6.9 g (180 mmol) of sodium borohydride in 250 ml of absolute ethanol, a solution of 15 g (73 mmol) of 2-chloro-3-formyl-7-methylquinoline in 250 ml of dry tetrahydrofuran was added over 15 minutes without cooling. During the addition a slight H2 -evolution and a temperature rise to +28° C. was observed. The reaction mixture was stirred at room temperature for 4 hours and then 4 ml of the reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate, extracted with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated in vacuo to give a residue of 100 mg. 1H-NMR indicated complete conversion to the alcohol. After 5 hours the whole reaction mixture was worked up in the same way to give 14.8 g 2-chloro-3-hydroxymethyl-7-methylquinoline after evaporation.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)[CH:9]=1)([O-:3])=[O:2].[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:11]3[N:12]=[C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]4[CH:10]=3)=[O:15])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: O=C(O)c1cn2cc([N+](=O)[O-])ccc2n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cc([N+](=O)[O-])ccc2n1
Yield: 18.9 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 6-nitroimidazo[1,2-a]pyridine-2-carboxylic acid (0.551 mmol, 0.114 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.459 mmol, 0.128 g). DMF (4 ml) was used as the solvent and HBTU (0.046 mmol, 0.017 g) was used instead of HOBt. The crude product was purified by preparative HPLC. 0.0405 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.37 (d, 3H), 4.30-4.37 (m, 1H), 4.38-4.46 (m, 1H), 4.59-4.72 (m, 1H), 6.72 (d, 1H), 7.54 (d, 1H), 7.68 (d, 1H), 7.72 (s, 1H), 7.78 (d, 1H), 8.15-8.21 (m, 1H), 8.38 (s, 1H), 10.40-10.44 (m, 1H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[N:20]=[CH:21][CH:22]=[N:23]5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1ccc2nccnc2c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5nccnc5c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoxaline-6-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoxaline.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][CH:5]1[O:14][CH3:15])=[N+]=[N-]>C(O)C.[Pd]>[CH3:13][S:10]([N:7]1[CH2:8][CH2:9][CH:4]([NH2:1])[CH:5]([O:14][CH3:15])[CH2:6]1)(=[O:12])=[O:11]
Reactant: COC1CN(S(C)(=O)=O)CCC1N=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: COC1CN(S(C)(=O)=O)CCC1N

Procedure:
The azide (270 mg, 1.15 mmol, Example 311) in ethanol was hydrogenated at 40 psi under the catalysis of palladium on carbon for 1 hour. The mixture was filtered and the filtrate was concentrated to give an off-white solid. 230 mg, 96%. It was used directly for the next step.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]#[N:19])=[C:5]2[N:10]([C:11]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][CH2:8][CH2:7][CH2:6]2)#[N:2].[OH-:20].[K+]>>[C:1]([C:3]1[C:4]([C:18]([NH2:19])=[O:20])=[C:5]2[N:10]([C:11]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][CH2:8][CH2:7][CH2:6]2)#[N:2]
Reactant: [OH-]
Reactant: N#Cc1c(C#N)c(-c2cccnc2)n2c1CCCC2
Agent: [K+]
Product: N#Cc1c(C(N)=O)c2n(c1-c1cccnc1)CCCC2

Procedure:
2-Cyano-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide is prepared according to the same method described in Example 11, from 2.12 g of 2-cyano-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 1.69 g of an aqueous solution of potassium hydroxide. 0.72 g of 2-cyano-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide are thus obtained in the form of a white solid melting at 244° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CCO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(Nc2ccccc2[N+](=O)[O-])CCCCC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1(Nc2ccccc2N)CCCCC1
Reaction time: 16 h
Yield: 98.9 %

Procedure:
A mixture of [1-(2-nitro-phenylamino)-cyclohexyl]-acetic acid methyl ester (230 mg, 0.79 mmol), 10% Pd/C (80 mg) in EtOH (20 mL) under H2 atmosphere at room temperature was stirred for 16 h. The reaction mixture was filtered and the organic layer was concentrated to give the desired [1-(2-amino-phenylamino)-cyclohexyl]-acetic acid methyl ester (205 mg, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@H:10]([CH:34]([CH3:39])[C:35]([O:37]C)=[O:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@H:10]([CH:34]([CH3:39])[C:35]([OH:37])=[O:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@H](C(C)C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate (56 mg, 0.094 mmol; Example 127, Step F) in MeOH/THF/H2O (1 mL/1 mL/2 mL) was added LiOH (3 M in water) (157 μL, 0.470 mmol) at room temperature. The slurry was heated to ˜100° C. for 3 h. The mixture was cooled to room temperature, acidified with 1 M HCl and extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The colorless film was purified by reverse phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes) to give the title compound.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16](=[C:19]1[CH2:22][CH:21]([C:23]([O-:25])=[O:24])[CH2:20]1)([CH3:18])[CH3:17].[CH2:26]([C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)[CH2:27][CH3:28]>ClCCl>[C:16](=[C:19]1[CH2:22][CH:21]([C:23]([O:25][C:38]2[CH:37]=[CH:36][C:35]([C@H:32]3[CH2:33][CH2:34][C@H:29]([CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31]3)=[CH:40][CH:39]=2)=[O:24])[CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)=C1CC(C(=O)[O-])C1
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](c2ccc(OC(=O)C3CC(=C(C)C)C3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.11 mol of DCC add 50 ml of dichloromethane is added at 0° C. to a mixture of 0.1 mol of 3-isopropylidenecyclobutanecarboxylate [sic] (prepared by the method of Gripps et al., Am. Soc. 81 (1959), 2723-2728) 0.1 mol of 4-(trans-4-propylcyclohexyl)phenol and 100 ml of dichloromethane. After the mixture has been stirred at room temperature for 16 hours and the solid constituents have been removed, conventional work-up gives the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[CH:4][C:3]=1[NH:28][C@H:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]1.FC1C(N[C@H]2CCC[C@@H](NC(=O)OC(C)(C)C)C2)=NC(C2C3C(=NC=C(F)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)=NC=1.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][C:3]=1[NH:28][C@H:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([NH2:35])[CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c3)c3cc(F)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Agent: Cl
Solvent: ClCCl
Product: N[C@@H]1CCC[C@H](Nc2cc(-c3c[nH]c4ncc(F)cc34)ccc2F)C1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (1R,3S)-3-(2-fluoro-5-(5-fluoro-1-tosyl-1H-pyrrolo-[2,3-b]pyridin-3-yl)phenylamino)cyclohexylcarbamate, 44d, (0.65 g, 1.09 mmol) in methylene chloride (22 mL) was added hydrogen chloride (2.71 mL of 4M solution in 1,4-dioxane, 10.86 mmol). The reaction was heated to 50° C. and stirred for 6 hours. The mixture was cooled to room temperature and concentrated in vacuo, producing a yellow solid. The crude residue was purified via silica gel chromatography (25-50% Ethyl Acetate/hexanes gradient). Desired fractions were combined and concentrated in vacuo to produce 350 mg of 44e as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[S:10](Cl)(Cl)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][S:10][N:9]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Clc1ccc2nsnc2n1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
6-Chloropyridine-2,3-diamine (Example 23, Step 1) (150 mg, 1.045 mmol) was taken-up in dioxane (21.0 ml) under argon at room temperature. Thionyl chloride (686 μl, 9.40 mmol) was added dropwise over 15 minutes. The mixture was then stirred at 75° C. for 24 hours. The reaction was quenched with water and extracted three times with ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel chromatography (0-65% ethyl acetate/hexanes) to afford 5-chloro[1,2,5]thiadiazolo[3,4-b]pyridine. LRMS (APCI) calc'd for (C5H3ClN3S) [M+H]+, 172. found 172.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([O-:24])=[O:23].N1C(C)=CC=CC=1C.[Na]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:31][C:28]3[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To the 7-benzyloxy-4-chloro-6-cyanoquinoline (2.60 g, 8.83 mmol) described in WO98/13350 there were added 4-nitrophenol (2.46 g, 17.7 mmol) and lutidine (2.06 ml, 17.7 mmol), and the mixture was heated and stirred at 155–158° C. for 2 hours. After returning the reaction system to room temperature, it was dissolved in tetrahydrofuran, saturated sodium bicarnobate water was added and stirred therewith for 10 minutes, the mixture was concentrated under reduced pressure, the precipitated solid was filtered out and subjected to silica gel column chromatography (Fuji Silysia NH Type, eluent—hexane:ethyl acetate=50:50→ethyl acetate alone), the fraction containing the target substance was concentrated and the obtained solid was washed with diethylether. It was then dried under reduced pressure to obtain the title compound (1.84 g, 4.63 mmol, 52.6%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])(=[O:39])=[O:38]
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)Cc1ccccc1CNS(C)(=O)=O)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 8a in dichloromethane (0.1 M) at 0° C. under nitrogen was added triethylamine (3.5 eq) and methanesulfonyl chloride (1.1 eq). The reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate (1×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (0-15% gradient methanol/dichloromethane) to afford the product. (41%) 1H NMR (400 MHz, CDCl3) δ 7.16-7.46 (m, 9H), 6.79 (m, 1H), 6.12 (m, 1H), 4.32 (m, 2H), 4.03 (m, 1H), 3.70 (m, 1H), 3.36-3.17 (m, 1H), 2.90 (s, 2H), 2.47-2.83 (m, 6H), 1.74 (m, 6H), 1.25 (m, 1H). Mass Spectral Analysis m/z=430.3 (M+H)+ tR=3.70 min (96%)
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([O:15][CH2:16]C)=[O:14])=[CH:11][N:12]=2)[CH:9]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1cnc2ccc(CC=O)cn12
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of crude ethyl 6-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxylate (112) (214 mg, 0.92 mmol) in DCM (5 mL) and 1-methylpiperazine (231 μL, 2.30 mmol) at room temperature was added portion-wise sodium triacetoxyborohydride (586 mg, 2.77 mmol). The reaction was stirred at room temperature overnight. The solvent was concentrated. The crude was taken in 10% sodium bicarbonate and ethyl acetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography to afford methyl 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylate (113). MS m/z 304.4 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]=[CH:23]N(C)C)=[CH:17][C:16]=1[N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30].C(OCC)(=O)C>C(O)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30]
Reactant: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1Cl)S(C)(=O)=O
Yield: 73 %

Procedure:
A mixture of 0.076 g (0.39 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.124 g (0.39 mmol) of (N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-N-methyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 128 mg of N-{2-chloro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 73%).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([C:18](=[O:37])[CH2:19][C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]2[CH2:38][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[O-]CC.[Na+].Cl>C(O)C>[OH:3][C:4]1[C@H:6]2[C@H:11]([C@H:10]3[CH2:38][C@@H:7]2[CH2:8][CH2:9]3)[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:18](=[O:37])[C:19]=1[C:20]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][C:23]=2[S:22](=[O:36])(=[O:35])[N:21]=1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Temperature: 60 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
The crude (1S,2R,3S,4R)-3-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester was dissolved in ethanol (7 mL) and a 21 wt. % solution of sodium ethoxide in ethanol (1.15 mL, 3.25 mmol) was added into the above solution. The mixture was stirred at 60° C. for 4 h and cooled down to 25° C. The mixture was poured into 0.5 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (Teledyne Isco RediSep column; 100% ethyl acetate) to afford the desired product, (1R,2S,7R,8S)-N-{3-[6-hydroxy-3-(3-methyl-butyl)-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.19 g, 0.364 mmol, 56.1% over two steps), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.89-0.93 (6H, m), 1.16-1.23 (2H, m), 1.28-1.32 (1H, m), 1.35-1.62 (7H, m), 1.99-1.99 (1H, m), 2.52-2.54 (1H, m), 2.63 (1H, bs), 3.06 (3H, s), 3.62-3.72 (2H, m), 7.50 (1H, dd, J1=8.9 Hz, J2=2.2 Hz), 7.57-7.59 (2H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C23H30N4O6S2 522.16, found 523.6 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.Cl.[CH3:13][NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CC(C)=O>[Cl:11][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:13])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CNCC(C)(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(C)(C)C)c1ncnc(Cl)c1[N+](=O)[O-]

Procedure:
4,6-Dichloro-5-nitro-pyrimidine (0.20 g, 1.0 mmol), N-methyl-neopentylamine hydrochloride (0.14 g) and DIEA (0.2 mL) were stirred in acetone (5 mL) at 0° C. for 4 hours. The solvent was removed in vacuo and the crude product was used for the next reaction without purification.
Reaction SMILES: [N:1]1[C:2](=[O:10])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl-].[Li+].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CN(C)C(=O)C>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]([CH2:13][CH:14]([OH:15])[CH2:16][OH:17])[C:2]1=[O:10]
Reactant: O=C1N=c2ccccc2=N1
Reactant: OCC1CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: O=c1n(CC(O)CO)c2ccccc2n1CC(O)CO
Temperature: 135 °C
Reaction time: 5 h

Procedure:
1.5 mols of benzimidazolone (201.2 g) are dissolved in 1.5 liters of N,N-dimethylacetamide at 120°C and 2.5 g of lithium chloride are added. 244.2 g (3.3 mols) of glycerol glycide (glycidol) are added dropwise over the course of 2 hours to this solution. The solution is then stirred for a further 5 hours at 135°C. After bringing the solution to room temperature, it is filtered and completely concentrated. The residue is dried for a further 5 hours at 95°C under 0.8 mm Hg. This gives 448 g of a brownish, very viscous liquid (theoretical yield: 423.5 g) which is the crude product still contaminated with a little dimethylacetamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=O)=[CH:4][CH:3]=1.Cl.[NH3:15]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:15])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: N
Agent: Cl
Product: NC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31 %

Procedure:
25% Aqueous ammonia (30 mL) was added to methyl 4-hydroxybenzenepropanoate (1.5 g, 8.3 mmol), and the mixture was stirred at room temperature for 15 hrs. Dil. hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.43 g, yield 31%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[N:3]1.[Br:8][CH:9]([CH:12]=O)[CH:10]=O>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]2=[N:7][CH:12]=1
Reactant: Cn1nccc1N
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: Cn1ncc2cc(Br)cnc21
Yield: 27.9 %

Procedure:
Dissolve 1-methyl-5-aminopyrazole (Butt Park LTD; 1.0 g, 10.3 mmol) and 2-bromomalonaldehyde (Aldrich; 1.55 g, 10.3 mmol) in glacial acetic acid (160 mL) and reflux under nitrogen for 48 h. Concentrate under reduced pressure and purify via chromatography (silica gel, 90% dichloromethane/10% diethyl ether) to obtain 610 mg (27%) of the title compound as an off-white solid. TOF MS ES+ exact mass calculated for C7H7N3Br (p+H): m/z=211.9823, Found: 211.9838.