Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Cl.[CH2:13]([NH:17][C:18](=[S:21])[NH:19][NH2:20])[CH2:14][CH2:15][CH3:16]>CO>[ClH:1].[CH2:13]([NH:17][C:18]1[S:21][CH2:5][C:4]([C:3]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])=[N:20][N:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNC(=S)NN
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CO
Product: CCCCNC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Product: Cl
Yield: 112.8 %

Procedure:
4.47 g of 2,4-dichlorophenacyl chloride and 2.66 g of 4-n-butyl-thiosemicarbazide are reacted under the conditions of Example 2 in 150 ml of methanol. The solid obtained is recrystallized from methanol/ethyl acetate, producing 3.98 g of N-butyl-5-(2,4-dichlorophenyl)-6H-1,3,4-thiadiazin-2-amine monohydrochloride. m.p. 180°-182° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][CH:6]([S:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:10])=[O:9])[CH2:5]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:16]([O:3][CH:4]1[CH2:7][CH:6]([S:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:10])=[O:9])[CH2:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCOS(=O)(=O)C1CC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOS(=O)(=O)C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
60% NaH (0.95 g, 2.52 (CH2)2CH3 mmol) was added to a cooled solution of butyl 3-hydroxycyclobutane-1-sulfonate (0.35 g, 1.68 mmol) in dry THF (20 mL) at 0° C. and the resulting reaction mass was stirred at room temperature for 30 minutes. This was followed by the addition of benzyl bromide (0.43 g, 2.52 mmol) and stirred the resulting mixture at room temperature for 2 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was quenched with ice-water and extracted using ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% ethyl acetate in hexane) afforded 0.2 g of the product (50% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1)[CH2:5][NH:6][C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:10][CH:9]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl.C(OCC)(=O)C>[C:40]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]3[CH:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:2]([F:1])[CH:3]=3)=[O:20])=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:42])[CH3:41]
Reactant: Cc1cc(-c2ccc(CNC(=O)c3ccc(N4CCNCC4)nc3)cc2F)ccn1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C(=O)NCc3ccc(-c4ccnc(C)c4)c(F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)-6-(piperazin-1-yl)nicotinamide 20-3 (10 mg, 0.025 mmol) and DIEA (21.8 μL, 0.125 mmol) in dichloromethane (1.0 mL) was added acetyl chloride (3.6 μL, 0.05 mmol), and the solution was stirred 30 minutes at room temperature. The solution was diluted with ethyl acetate (30 mL) and washed with 10% Na2CO3 aqueous solution and water. After the organic phase was dried over Na2SO4, the solvent was evaporated under reduced pressure and the residue subjected to preparative reverse phase HPLC to give 6-(4-acetylpiperazin-1-yl)-N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)nicotinamide 20 as a solid. MS m/z 448.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.63 (d, 1H), 8.54 (d, 1H), 7.98 (dd, 1H), 7.42 (dd, 1H), 7.33 (bs, 1H), 7.29-7.25 (m, 1H), 7.22 (dd, 1H), 7.16 (dd, 1H), 6.64 (d, 1H), 6.61 (t, 1H), 4.67 (d, 2H), 3.78-3.70 (m, 4H), 3.65-3.54 (m, 4H), 2.61 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:32](Cl)=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=2)=[O:30])=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][NH:1][C:36]1[C:31]([C:29](=[O:30])[NH:28][C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)=[CH:32][N:33]=[C:34]([S:37][CH3:38])[N:35]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)OC(C)(C)C)n1
Reaction time: 8 h
Yield: 80.6 %

Procedure:
tert-Butyl N-(2-aminoethyl)carbamate (0.500 g, 3.12 mmol) and DIPEA (0.83 mL, 4.68 mmol, 1.5 eq) was added to a solution of 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (0.929 g, 3.12 mmol) in DMF (5.0 ml) and stirred under N2 overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed twice with water (50 mL). Upon precipitation of product out of the organic layer of the mixture, the white solid was filtered, and recrystallized from hot ethyl acetate to yield 1.06 g (80%) of the titled product as a white solid. 1H NMR: (d6-DMSO) δ 10.21 (s, 1H), 8.56 (s, 1H), 7.64 (m, 2H), 7.16 (m, 2H), 6.92 (t, 1H), 3.48 (m, 2H), 3.30 (s, 3H), 3.11 (m, 2H), 1.31 (s, 9H); HPLC: Rt=4.32 min; MS (ESI): m/z 419.97 (M−H)−.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH2:14]([N:21]1[CH2:30][CH2:29][C:28]2[N:27]=[C:26](Cl)[CH:25]=[CH:24][C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([O:36][C:37](=[O:40])[CH:38]=[CH2:39])([CH3:35])([CH3:34])[CH3:33]>O1CCOCC1.C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]([N:21]1[CH2:30][CH2:29][C:28]2[N:27]=[C:26](/[CH:39]=[CH:38]/[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])[CH:25]=[CH:24][C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Tri-tert-butylphosphine (3.0 g, 15.28 mmol) was added to a solution of tris(dibenzylideneacetone)dipalladium (4.2 g, 4.63 mmol) in 1,4-dioxane (45 ml), under argon, and the solution stirred for 30 minutes at room temperature. This solution was then added to a mixture of 6-benzyl-2-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine (WO 9830560 Example 33b) (12 g, 46.3 mmol) and tert-butylacrylate (20.3 ml, 139 mmol) in triethylamine (45 ml), and the reaction was stirred under reflux for 17 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (300 ml) and water (300 ml) and this mixture filtered through Arbocel®. The pH of the mixture was adjusted to 8 using sodium bicarbonate, the phases separated, and the aqueous layer re-extracted with ethyl acetate (2×100 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The crude product was pre-adsorbed onto silica gel, and purified by column chromatography using an elution gradient of cyclohexane: ethyl acetate (84:16 to 66:34) to afford the title compound as an orange-red oil, (15.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:51][C@:52]1([C:62]([O:64][CH3:65])=[O:63])[CH2:54][C@@H:53]1[C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1>CN(C=O)C>[Br:61][C:58]1[CH:57]=[CH:56][C:55]([C@H:53]2[CH2:54][C@:52]2([NH:51][C:14]([C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[C:62]([O:64][CH3:65])=[O:63])=[CH:60][CH:59]=1
Reactant: COC(=O)[C@@]1(N)C[C@@H]1c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@]1(NC(=O)[C@@H]2CCCCN2C(=O)OC(C)(C)C)C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (9.05 mg) in DMF (3 mL) was added Hunig's Base (0.019 mL) followed by HATU (15 mg). The mixture was allowed to stir at room temp for 10 min. To this solution was added in one portion (1R,2R)-methyl 1-amino-2-(4-bromophenyl)cyclopropanecarboxylate hydrochloride (11 mg) and the mixture was stirred overnight. The mixture was evaporated to dryness, the residue extracted into diethyl ether and washed well with water and brine, then dried over sodium sulfate. The sample was passed through a small silica plug/eluting with diethyl ether to give (S)-tert-butyl 2-((1R,2R)-2-(4-bromophenyl)-1-(methoxycarbonyl)cyclopropylcarbamoyl)piperidine-1-carboxylate (6 mg) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>ClCCl>[N+:12]([C:3]1[C:4]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[N:5][C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc2ccccc2nc1NCCCCO
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a stirred mixture of 4-chloro-3-nitroquinoline (100.0 g, 479 mmol) and triethylamine (72.8 g, 719 mmol) in dichloromethane (700 mL) was added dropwise 4-amino-1-butanol (42.7 g, 479 mmol). After the addition was complete, water (500 mL) was added to the reaction mixture to cause the product to precipitate. More water (2 L) was added, and the mixture was stirred overnight and then filtered. The organic solution was dried over sodium sulfate, concentrated under reduced pressure, and combined with the product isolated by filtration to provide 4-(3-nitroquinolin-ylamino)butan-1-ol (113 g) as a bright yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[N:6]=[C:7]([NH2:19])[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=1.[S:20]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21]1.CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C.O>[NH2:19][C:7]1[C:8]2[N:9]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:10]=[C:5]([C:4]#[C:3][CH2:2][NH:1][S:25]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)(=[O:27])=[O:26])[N:6]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: NCC#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(C#CCNS(=O)(=O)c2ccsc2)cn2nc(-c3ccco3)nc12
Reaction time: 8 h

Procedure:
To a solution of 6-(3-amino-prop-1-ynyl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine (0.1 mmol, see Example 26 below) in THF (1 mL) was added thiophene-3-sulfonyl chloride (23.7 mg, 0.13 mmol), a catalytic quantity of DMAP and Hünig's base (52 uL, 0.3 mmol) successively. The reaction was stirred overnight and diluted with water. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvent was then evaporated. The residue was purified using preparative HPLC (C18, H2O:MeCN gradient) to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ8.16 (1H), 8.09 (1H), 7.86 (1H), 7.68 (1H), 7.54 (1H), 7.31 (1H), 7.07(1H), 6.65 (1H), 4.23 (2H), 3.53 (d, J=7 Hz, 2H). MS: m/z 401 [M+1].
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.O[CH:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][CH:32]4[CH2:36][CH2:35][O:34][C:33]4=[O:37])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1OCCC1O
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC3CCOC3=O)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 1) (203 mg, 0.5 mmol), 3-hydroxyoxolan-2-one (CAS no. 19444-84-9) (0.078 mL, 1 mmol) and triphenyl phosphine (262 mg, 1 mmol) in anhydrous THF (10 mL) under argon at 0° C. was treated dropwise with DIAD (0.20 mL, 1 mmol). The mixture allowed to warm to room temperature and stirred for 16 hours. The solvent was removed by evaporation under reduced pressure and the residue was purified by chromatography on silica eluting with 0-4% methanol:DCM to give product (212 mg 86%). 1H NMR δ (400 MHz, CDCl3) 2.29 (quintet, 2H), 2.40-2.48 (m, 1H), 2.50 (s, 3H), 2.69-2.78 (m, 1H), 4.18 (t, 2H), 4.33 (q, 1H), 4.49 (t, 1H), 4.64 (t, 2H), 4.99 (t, 1H), 6.89 (s, 1H), 7.18 (s, 1H), 7.33 (d, 1H), 7.36 (s, 1H), 8.06 (d, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.41 (s, 1H), 9.46 (s, 1H); m/z 490 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:26]2[S:30][C:29]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12]([C:26]3[S:30][C:29]([CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(CN3CCCC3)s2)OC1(C)C
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(CN3CCCC3)s2)nc1C(=O)Nc1ccncc1

Procedure:
The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acid pyridin-4-ylamide (synthesis described for “A10”) with 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-pyrrolidine gives the compound “A14”;
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[I:12][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]=[C:2]([I:1])[C:10]=1[OH:11]
Reactant: NCCCCCCCCc1ccccc1
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(I)c(O)c(I)c1

Procedure:
The title compound was prepared as a solid (0.718 g, 66%) from 3,5-diiodo-4-hydroxybenzoic acid using 8-phenyloctylamine and a procedure similar to step 2 of Example 93; 1H NMR (DMSO-d6) δ 1.17-1.36 (m, 8H), 1.41-1.61 (m, 4H), 2.48-2.60 (m, 2H), 3.20 (dd, J=5.9, 8.8 Hz, 2H), 7.10-7.21 (m, 3H), 7.21-7.30 (m, 2H), 8.21 (s, 2H), 8.40 (t, J=4.4 Hz, 1H), 10.06 (s, 1H); mass spectrum [(+) ESI], m/z 578 (M+H)+.
Reaction SMILES: N=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[NH:8][C:9]([N:11]1C=CN=C1)=[S:10].Cl[CH2:17][C:18]1[N:19](C)[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:22]=1.[CH2:30](O)CC>>[CH3:30][SH:10]([CH2:17][C:18]1[NH:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:22]=1)[C:9]1[N:11]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][N:3]2[N:8]=1
Reactant: CCCO
Reactant: N=c1ccccn1NC(=S)n1ccnc1
Reactant: Cn1cc(-c2ccccc2)nc1CCl
Product: C[SH](Cc1nc(-c2ccccc2)c[nH]1)c1nc2ccccn2n1
Yield: 62 %

Procedure:
An adaptation of the method described in WO 96/01826 was used. Imidazole-1-carbothioic acid (2-imino-2H-pyridin-1-yl)-amide (200 mg, 1.37 mmol) and 2-chloromethyl-1-methyl-4-phenyl-1H-imidazole 6 (300 mg, 1.46 mmol) were dissolved in 1-propanol (25 mL) and the mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with water and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel to afford the title compound (273 mg, 62%) as a yellow solid. LC-MS: m/z=322.1 (MH+), tR=2.29 min, method B.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[CH:17][CH:18]=1)[N:8]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[N:10]=2.C(N(CC)CC)C.Cl[C:27]1[N:36]=[C:35]([NH2:37])[C:34]2[C:29](=[CH:30][C:31]([O:40][CH3:41])=[C:32]([O:38][CH3:39])[CH:33]=2)[N:28]=1>C(O)CCC>[N:8]1[C:7]2=[CH:17][CH:18]=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][C:9]=1[N:11]1[CH2:16][CH2:15][N:14]([C:27]2[N:36]=[C:35]([NH2:37])[C:34]3[C:29](=[CH:30][C:31]([O:40][CH3:41])=[C:32]([O:38][CH3:39])[CH:33]=3)[N:28]=2)[CH2:13][CH2:12]1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: Clc1ccc2nc(N3CCNCC3)nc-2cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5cccccc-5n4)CC3)nc(N)c2cc1OC
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 2-(1-piperazinyl)cycloheptimidazole hydrochloride (4.53 g, described in Example 1) and triethylamine (3.64 g) in butanol (500 ml) was stirred for one hr and 2-chloro-4-amino-6,7-dimethoxyquinazoline [4.35 g, prepared as described by T. H. Althius and H.-J. Hess, J. Med. Chem., 20, 146 (1977)] was added. The mixture was refluxed for 18 hr. The resulting precipitate was collected on a filter. The filtrate was evaporated to dryness. A suspension of the precipitate and the evaporated filtrate in a cold, aqueous solution of sodium bicrbonate (5% w/v) was stirred for 30 min and filtered. The precipitate was washed with water, air-dried and crystallized from methanol-dichloromethane to give the title compound (6.3 g): mp 294°-296° C.; ir (nujol mull) 3300, 3180, 1650, 1625, 1598 and 1560 cm-1 ; uv max (MeOH) 251 nm (ε=63670); nmr (DMSO-d6) δ 3.85 (m, 14H) and 7.4 (m, 7H); and Anal. Calcd for C22H23N7O2 : C, 63.29% H, 5.55% N, 23.49% and Found: C, 62.96% H, 5.60% N, 23.61%.
Reaction SMILES: [Cl:1][C:2]1C=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[NH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C([N:42](CC)CC)C>O1CCOCC1.CN(C=O)C.C(OCC)(=O)C>[C:31]([C:29]1[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:25]([O:24][CH2:23][CH2:22][NH:21][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:42]=3)[CH2:13][CH2:12]2)=[O:16])[CH:30]=1)#[N:32]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CCc1ccc(C#N)cc1OCCN
Reactant: CCOC(=O)C1CCN(c2ccnc(Cl)c2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc(C#N)cc1OCCNC(=O)C1CCN(c2ccnc(Cl)n2)CC1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
700 mg (2.60 mmol) of ethyl 1-(2-chloropyridine-4-yl)-4-piperidinecarboxylate was stirred in 5 ml of dioxane. 5 ml of 2 N hydrochloric acid was added to the obtained mixture, and they were stirred at 95° C. for 4 hours. The solvent was evaporated, and the obtained crude product was dissolved in 10 ml of DMF. 600 mg (2.16 mmol) of ethyl 3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 548 mg (3.24 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.9 ml (6.48 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br>C(#N)C>[CH3:12][CH:11]([CH3:13])[CH2:10][C@H:2]([N:1]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1CCOCC1
Temperature: 80 °C

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate (1.0042 g, 5.36 mmol), potassium carbonate (2.446 g, 17.69 mmol), and 1-bromo-2-(2-bromoethoxy)ethane (1.368 g, 5.90 mmol) were combined in acetonitrile (30 mL). The reaction was heated at 80° C. overnight. The reaction was cooled and filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography using 5-50% ethyl acetate/hexanes to give (S)-tert-butyl 4-methyl-2-morpholinopentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.76-3.58 (m, 4H), 3.11 (dd, J=6.9, 8.1, 1H), 2.74-2.53 (m, 4H), 1.71-1.55 (m, 2H), 1.51-1.34 (m, 10H), 0.92 (dd, J=6.6, 7.3, 6H). (S)-tert-Butyl 4-methyl-2-morpholinopentanoate (0.637 g, 2.475 mmol) and 4 N hydrochloric acid in dioxane (5 mL) were combined. The reaction mixture was stirred at ambient temperature for 24 hours, then the solvent removed in vacuo to give (S)-4-methyl-2-morpholinopentanoic acid hydrochloride: MS (DCI+) m/z 202 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:16]C)[C:6](=[O:18])[C:5]=2[CH:4]=1.C1(=O)C2C(C3C(C=2)=CC=CC=3)=CC=C1.Br>C(O)(=O)C.C(Cl)Cl>[OH:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[OH:16])[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)c1cccc(OC)c1-2
Agent: Br
Agent: O=C1C=CC=C2C1=Cc1ccccc12
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1c2cc(O)ccc2-c2c(O)cccc21
Temperature: 80 °C

Procedure:
Prepare a solution of 2,5-dimethoxy-fluoren-9-one (7.5 g, 0.031 mmole) in 50 mL glacial acetic acid and warm to 80° C. Once all of the fluorenone goes into solution, add 150 mL hydrogen bromide (48% solution). Continue heating to reflux, redissolving any precipitate formed, and reflux overnight. Cool to room temperature and filter. Wash the filtrate with water. Take-up the solids in ethyl acetate and dissolve by heating in a steam bath. Filter through a short column of silica, eluting with hot ethyl acetate. Condense the ethyl acetate eluent on a rotary evaporatory to obtain a dark red solid. Heat in hot methylene chloride to dissolve undesired solid and filter to obtain 2,5-dihydroxy-fluoren-9-one. m.p. 298-301 dec. (Yield 9.4 g, 97%).
Reaction SMILES: [CH2:1]=O.[NH:3]([CH3:5])[CH3:4].CO.[CH3:8][O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][N:16]2[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:12][C:11]=1[OH:28]>CCO>[CH3:4][N:3]([CH2:1][C:12]1[C:11]([OH:28])=[C:10]([O:9][CH3:8])[CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][N:16]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:5]
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1O
Reactant: CNC
Reactant: C=O
Solvent: CO
Solvent: CCO
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c(CN(C)C)c1O
Temperature: 80 °C

Procedure:
Paraformaldehyde (28 mg, 0.932 mmol) and 2 M Me2NH in MeOH (0.47 ml, 0.932 mmol) was heated until clear solution was obtained. The solution was added to 6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol (61 mg, 0.201 mmol; Intermediate 101) in EtOH (1.5 ml) and the mixture was heated in microwave oven at 80° C. for 10 min. A small part was purified on Gilson HPLC using 25-55% MeCN in 50 nM ammonium hydrogencarbonate as eluent. Yield: 3.8 mg; white solid. MS (ESI+) for C18H20N2O4S m/z 361 (M+H)+.