Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[N:3]1[C:7]2([CH2:12][CH2:11][N:10]([N:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]2)[C:6](=[O:16])[CH:5]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[C:4]1=[O:26].C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O1CCCC1>[CH2:39]([O:38][C:36](=[O:37])[O:16][C:6]1[C:7]2([CH2:12][CH2:11][N:10]([N:13]([CH3:14])[CH3:15])[CH2:9][CH2:8]2)[N:3]([N:2]([CH3:1])[CH3:27])[C:4](=[O:26])[C:5]=1[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)N(N(C)C)C3(CCN(N(C)C)CC3)C2=O)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(N(C)C)C12CCN(N(C)C)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
150 mg 1,8-Bis-dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione (PREPARATION EXAMPLE 1) is dissolved in 3 ml tetrahydrofuran, 75 mg triethylamine is added, and the mixture is cooled to 0° C. 44 mg ethyl chloroformate is added and the resulting suspension stirred for 3 hours, thereby warming to room temperature. Then the mixture is partitioned between water and ethyl acetate, the organic layer separated and washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue is purified by chromatography on silica gel with ethyl acetate/heptane (1:1) as a solvent. Thus, 145 mg Carbonic acid 1,8-bis-dimethylamino-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester ethyl ester is obtained as a solid, mp 105° C. 1H-NMR (CDCl3): 6.83 ppm (s, 2H), 4.02 ppm (q, 2H), 3.05 ppm (m, 2H), 2.94 ppm (s, 6H), 2.80 ppm (m, 2H), 2.43 ppm (s, 6H), 2.40 ppm (m, 2H), 2.23 ppm (s, 3H), 2.17 ppm (s, 6H), 1.86 ppm (m, 2H), 1.08 ppm (t, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]2[C:13]([OH:15])=[O:14])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O[C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40])=O>CN(C=O)C>[F:36][C:35]1[C:30]([O:14][C:13]([C:6]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=2)=[O:15])=[C:31]([F:40])[C:32]([F:39])=[C:33]([F:38])[C:34]=1[F:37]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)c1cc([N+](=O)[O-])cn1CC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc([N+](=O)[O-])cn1CC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
To a solution of 1-cyclopropylmethyl-4-nitro-1H-pyrrole-2-carboxylic acid (8.07 g, 38.39 mmol) in anhydrous DMF (120 ml) in the presence of N,N-diisopropylethyl-amine (7.69 ml) was added dropwise pentafluorophenyl trifluoroacetate (7.59 ml, 44.15 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 5 h. After removal of solvent, the crude product was purified by chromatography on silica gel eluted by toluene-ethyl acetate (50:1) to give compound 278 (14.28 g, 98%) as a white powder. H1-NMR (DMSO-d6) 8.58 (d, 1H), 7.84 (d, 1H), 4.22 (d, 2H), 1.32−1.06 (m, 1H), 0.55–0.51 (m, 2H), 0.45−0.42 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([N:25]3[CH2:29][CH2:28][NH:27][C:26]3=[O:30])[CH:3]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:5]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: O=C1NCCN1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCNC2=O)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
150 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine (Example 9), 224 mg of 2-imidazolidinone, 26 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 185 mg of tripotassium phosphate and 23 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 5 ml of degassed 1,4-dioxane, and then the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed with water, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 80 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidin-4-yl}imidazolidin-2-one as white powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 56 mg of the objective compound as pale yellow powder.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(CO)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(CO)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 45.3 %

Procedure:
1.29 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.451 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropanol were stirred at 190-200° C. for 90 minutes. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected; the residue was recrystallized from ethyl ether to yield 0.465 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[NH:15][C:14]=1[CH:26]=O.[CH2:28](O)[CH3:29]>N1CCCCC1>[CH3:12][C:13]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])[NH:15][C:14]=1[CH:26]=[C:10]1[C:3]2[C:2]([N:5]3[CH2:29][CH2:28][CH2:2][CH2:3][CH2:4]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9]1=[O:11]
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=O
Reactant: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(N3CCCCC3)c21
Yield: 79 %

Procedure:
A mixture of 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (169 mg, 1 mmol), 3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (222 mg, 1 mmol) and piperidine (2 drops) in ethanol (3 mL) was heated to reflux for overnight. The precipitate was collected by vacuum filtration, washed with ethyl acetate/hexane and dried to give 332.2 mg (79%) of the title compound as a yellow solid. MS 423 [M++1].
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1>>[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH:17][C:1]2[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=[C:3]([N:18]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]3)[CH:2]=2)[CH:13]=1
Reactant: OC1CCNCC1
Reactant: N#CC=Cc1ccccc1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2cc(N3CCC(O)CC3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 101 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and O-protected piperidin-4-ol. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2c(Oc3ccc(C)cc3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Oc2cccc3[nH]c(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
140 (70 mg, 0.237 mmol) is dissolved in 5 ml of methanol and treated with a solution of LiOH (11.4 mg, 0.474 mmol) in 3 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][CH:50]=1>C1COCC1>[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:57][C:47]=2[C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[N:49][CH:50]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:14]([NH2:17])[CH:15]=[CH2:16].[OH-].[Na+]>C1COCC1.Cl>[CH2:14]([NH:17][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH:15]=[CH2:16]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C=CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCNS(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a solution of 3-(chlorosulfonyl)benzoic acid (5 g, 22.66 mmol) in THF (50.4 mL) at 0° C. was added allylamine (2.038 mL, 27.2 mmol) followed by NaOH (1N aqueous) (49.9 mL, 49.9 mmol). The mixture was allowed to warm to RT over 1 hour and stirred an additional 16 hours. The mixture was diluted with 1N HCl (250 mL), and the aqeuous layer was extracted with EtOAc (300 mL). The organic layer was dried over sodium sulfate and concentrated to dryness to afford 3-(N-allylsulfamoyl)benzoic acid as white solid (5.2 g, 95% yield). MS m/z=242.0 [M+H]. Calc'd for C10H11NO4S: 241.0.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]12[C:25]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23](=[O:30])[O:22][C:20](=[O:21])[C:19]1=[CH:31][CH:32]=[CH:33][CH:34]=2>C1(C)C=CC=CC=1>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:18]3[C:19]([C:20]([OH:22])=[O:21])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:30])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCC(c2ccccc2)CC1
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1-c1ccccc1C(=O)NCCCN1CCC(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
4-Phenyl-1-piperidinepropanamine, hydrochloride (prepared in part A) (16.33 g, 53.5 mM) and diphenic anhydride (12.0 g, 53.5 mM) are refluxed in toluene for 2 hours. The mixture is allowed to stand overnight at room temperature during which time product crystallizes out. The crystals are filtered off, washed with toluene, recrystallized from ethanol, and dried at 80° to give the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[C-:17]#[N:18].[Na+].O>CN(C)C=O>[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:17]#[N:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCCCCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCCc1ccccc1
Yield: 949.6 %

Procedure:
A stirred solution of 15.0 grams (0.0062 mole) of 1-methylsulfonyloxy-5-phenylpentane and 9.1 grams (0.190 mole) of sodium cyanide in 150 mL of N,N-dimethylformamide was heated at 50° C. to 55° C. for about 60 hours. After this time the reaction mixture was poured into 400 mL of water. The mixture was extracted with three 250 mL portions of diethyl ether. The combined extracts were then washed with three 200 mL portions of water and 200 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.2 grams of 6-phenylhexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]1[O:54][C:53](=[O:55])[NH:52][CH2:51]1)[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:50]4[O:54][C:53](=[O:55])[NH:52][CH2:51]4)([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C5CNC(=O)O5)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C5CNC(=O)O5)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
To a solution of 5-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]oxazolidin-2-one 27a (113 mg, 0.17 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.1 mL, 0.85 mmol) and 10% Pd/C (20 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filter cake was washed with a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL×2). The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/1 to give the title compound 27 as a white solid (66.2 mg, 78.8%, HPLC: 90.1%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 492.2 [M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.54 (s, 1H), 7.42 (m, 2H), 7.31 (m, 1H), 7.16 (m, 2H), 7.34 (m, 2H), 5.68 (d, 1H), 5.18 (d, 2H), 4.81 (t, 1H), 4.11 (m, 1H), 3.98 (m, 4H), 3.69 (t, 1H), 3.48 (m, 3H), 3.30 (m, 1H), 3.21 (m, 1H), 1.32 (t, 3H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].CN(C)C=O.[OH-].[K+].[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1S(C)(=O)=O>O>[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[C:13]1[S:3][CH2:1][CH3:2]
Reactant: Cn1cc([N+](=O)[O-])nc1S(C)(=O)=O
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc([N+](=O)[O-])cn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Ethyl mercaptan (5.14 g, 0.083 mole) was added to dimethylformamide (140 ml) containing potassium hydroxide (4.6 g, 0.08 mole). This was stirred for 90 minutes until all the potassium hydroxide had dissolved. To this solution was added 1-methyl-2-methylsulfonyl-4-nitroimidazole (8.5 g, 0.04 mole) and the reaction stirred for 2 hours at room temperature. The reaction mixture was then added to water (500 ml) and stirred in an ice bath for an additional hour. The crystalline product was filtered off and dried to give 5.6 g of crude product. This was recrystallized from ethanol/water to give 4.3 g of product.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([CH3:12])[C:8]=2[CH:13]=1)N.[CH:14]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([CH2:16][CH3:17])[CH3:15].C(O)(C)C.Cl>C(O)(C)C>[CH:14]([N:18]1[CH2:23][CH2:22][C:21]2[NH:2][C:4]3[C:13]([C:20]=2[CH2:19]1)=[C:8]1[C:9]([CH3:12])=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)([CH2:16][CH3:17])[CH3:15]
Reactant: Cc1csc2ccc(NN)cc12
Reactant: CCC(C)N1CCC(=O)CC1
Agent: Cl
Solvent: CC(C)O
Product: CCC(C)N1CCc2[nH]c3ccc4scc(C)c4c3c2C1

Procedure:
11 g of 5-hydrazino-3-methylbenzothiophene hydrochloride and 8.5 g of 1-sec.-butyl-4-piperidone are boiled in 35 ml of isopropanol, and during this procedure isopropanol/HCl are added dropwise. The mixture is then evaporated, the residue is taken up in water and the mixture is rendered alkaline and extracted with methylene chloride. After washing and drying the organic phase, it is evaporated and the residue is recrystallised from cyclohexane. Melting point: 136°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH2:19]O)=[C:7]([Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13])[NH:8]2)=[CH:4][C:3]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>C1COCC1>[Br:41][CH2:19][CH2:18][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[C:3]([CH3:21])[CH:4]=2)[NH:8][C:7]=1[Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCBr
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution 2-(6-chloro-5-methyl-2-(triethylsilyl)-1H-indol-3-yl)ethanol (1.44 g; 4.45 mmol) in THF (6 mL) was added to a solution of triphenyl phosphine (1.75 g; 6.67 mmol) and perbromomethane (2.21 g; 6.67 mmol) in THF (40 mL) pre-stirred for 30 minutes. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford 0.725 g (42%) of the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([NH2:27])=[O:26]>>[C:25]([C@@H:24]([NH:23][C:14]([C:12]1[CH:11]=[CH:10][C:9]([N:17]2[CH2:20][C:19]([F:21])([F:22])[CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:26])[NH2:27]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(-c2cccc(Cl)c2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=437.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.Cl[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:21]>>[C:24]([CH2:23][CH2:22][C:20]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)=[O:21])([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCC(=O)Cl
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: COC(=O)CCC(=O)n1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-(3-Carbomethoxypropionyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and methyl 3-(chloroformyl)propionate.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:40]2[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[NH:3][C:4](=[O:7])[O:5][N:47]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(-c2ccccc2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(-c2ccccc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-[(5-oxo-4-phenyl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.61 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.34 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([O:25]CC)=O)[O:20][N:19]=2)=[CH:4][CH:3]=1.[NH2:28][NH2:29].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:28][NH2:29])=[O:25])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Solvent: O
Solvent: CO
Product: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 3-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate (10.5 mmol, 4.0 g) in MeOH (50 mL) was cooled to 0° C., and 99% NH2NH2.H2O (62.8 mmol, 3.2 g) was then added dropwise. In the period of addition, lots of white precipitate was generated, kept stirring for 15 mins, the white solid was collected by filtration. The white solid was dispersed into MeOH again, sonicated for 10 mins, filtered, to give the final product (3.3 g, 86.0%). m/e+=369 (M+H+). 1H NMR (400 MHz, in DMSO-d6): δ 10.9-10.5 (1H, D, brd, NH), δ 8.44-8.42 (1H, D, d, J=6.8 Hz, ArH), δ 7.87-7.85 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.67-7.64 (1H, D, d, J=9.2 Hz, ArH), δ 7.56-7.54 (2H, D, dd, J=6.4, 1.6 Hz, ArH), δ 7.38-7.25 (1H, D, m, ArH), δ 5.01-4.75 (2H, D, brd, NH2), δ 4.75 (2H, D, s, CH2).