Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=[N:3]1.[CH3:14][N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>>[C:8]1([S:7][C:6]2[N:2]([O:1][C:16](=[O:17])[N:15]([CH3:14])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:3]=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: On1nccc1Sc1ccccc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1nccc1Sc1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-5-phenylsulfanylpyrazole and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (80%, oil).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c2c(c(=O)n(-c3cc(C(=O)O)c(Cl)cc3F)c1=O)CCC2
Reaction time: 15 h

Procedure:
A solution of 26.6 g of isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 1.7 l of methanol is treated with a solution of 3.08 g of sodium hydroxide in 700 ml of water. The reaction mixture is stirred at room temperature for 15 hours, during which 2.1 l of water are continuously added dropwise. Stirring is continued for a further 15 hours during which the pH value of the mixture reaches 9-10. The mixture is acidified with concentrated hydrochloric acid and concentrated under reduced pressure at approx. 20° C. to a volume of approx. 300 ml. The crystals are filtered off by suction, rinsed with a little water and dried at 40°-50° C. under reduced pressure. 2-Chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoic acid, m.p. 270°-273° C., is obtained.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][Cl:14])=[CH:4][C:3]=2[O:2]1.[ClH:16].Cl.[CH2:18]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[ClH:14].[ClH:16].[CH2:18]([N:27]1[CH2:32][CH2:31][N:30]([CH2:13][C:12]([NH:11][CH2:10][C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[O:15])[CH2:29][CH2:28]1)[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: O=C(CCl)NCc1ccc2c(c1)OCO2
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CN1CCN(CC(=O)c2ccccc2)CC1)NCc1ccc2c(c1)OCO2

Procedure:
A mixture of N-[1-(3,4-methylenedioxyphenyl)methyl]-2-chloroacetamide (5 mmol), N-phenacyl piperazine dihydrochloride (5 mmol) and K2CO3 (17.5 mmol) in 60 ml of acetone was treated according to the general preparation 2 to give compound (IV-32), 0.76 g (63.45%), M+ 395.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]=[C:60]2[CH2:66][CH2:67][NH:68][C:69]1[N:77]=[C:76]([C:78]2[C:79]3[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=3[S:81][CH:82]=2)[N:75]=[C:74]2[C:70]=1[N:71]=[CH:72][N:73]2[CH:87]([CH3:89])[CH3:88])=[O:55]>CN(C=O)C>[O:14]=[C:13]1[NH:12][C@H:11]2[CH2:10][S:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:2]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]3[CH:58]=[C:59]4[C:63](=[CH:64][CH:65]=3)[NH:62][CH:61]=[C:60]4[CH2:66][CH2:67][NH:68][C:69]3[N:77]=[C:76]([C:78]4[C:79]5[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=5[S:81][CH:82]=4)[N:75]=[C:74]4[C:70]=3[N:71]=[CH:72][N:73]4[CH:87]([CH3:89])[CH3:88])=[O:55])=[O:3])[C@H:16]2[NH:15]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCN)cc34)nc(-c3csc4ccccc34)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)CCCC[C@@H]5SC[C@@H]6NC(=O)N[C@@H]65)cc34)nc(-c3csc4ccccc34)nc21
Reaction time: 0.17 h

Procedure:
To a solution of (+)-biotin (35 mg, 0.14 mmol) and Et3N (36 mg, 0.35 mmol) in DMF (1 ml) was added HATU (90 mg, 0.24 mmol). The mixture was stirred for 10 min, and then was added to a solution of (3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-yl 6-aminohexanoate (b) (68 mg, 0.12 mmol) in DMF (1 ml). The reaction mixture was stirred for 16 hr at rt and then was concentrated. The residue was purified by reverse-phase HPLC (C18 column, eluting with MeOH—H2O 0.05% TFA) to afford the title compound as an off-white solid. Example 210 showed an EC50 value in the % CD34+ assay of 2.1 μM.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][C:4]([CH3:11])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)O)c(O)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)c(=O)[nH]1
Temperature: -70 °C
Reaction time: 1 h
Yield: 110.6 %

Procedure:
2-hydroxy-6-methylpyridine-3-carboxylic acid (2 g, 13 mmol) was dissolved in dry THF (80 ml), and this solution was cooled to −70° C. LiAlH4 (32 ml, 32 mmol) was then added over a period of 20 min. The reaction mixture was warmed to room temperature and then was heated at 70° C. for 1 hour. After cooling down to 0° C., the reaction mixture was added H2O (2 mL), 10% NaOH (4 mL) and finally H2O (2 mL). The reaction mixture was stirred at room temperature for 1 hour. NaSO4 (6 g) was added, the mixture was stirred for a further 30 min., filtered and washed with MeOH. The filtrate was concentrated to dryness to give the desired product as a solid (2 g, 100%). LCMS (ES+) m/z 140 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:22](OCC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[C:8]([C:7]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])([CH2:6][C:5]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]#[N:14])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Yield: 82 %

Procedure:
A solution of ethyl 3,4,5-trimethoxybenzylcyanoacetate (14.7g) in triethyl orthoformate (100 ml) was heated at reflux for 18 hours using a steam-jacketed column for continuous removal of ethanol. The solution was cooled, and most of the excess orthoformate was removed in vacuo. The crystals obtained were washed with ether and dried to yield colourless crystals of α-carbethoxy-α-diethoxymethyl-β-(3,4,5-trimethoxy phenyl)propionitrile (16.3 g, 82%), m.p. 91θ ; nmr (CDCl3) δ1.13, 1.20. and 1.32 (triplets, 9, CH3CH2O-), 3.15 (s, 2, Ar-CH2 -C), 3.4-4.0 (m, 4, m, 4, CH3CH2 -O), 3.85 (s, 9, -C6H2 -(OCH3)3), 4.13 (q, 2, CH3CH2 -OCO), 4.80 (s, 1, -CH (OEt)2), and 6.55 (s, 2, aromatic H). Anal. Calcd. for C20H29NO7 : C, 60.74; H, 7.39; N, 3.54. Found: C, 60.56; H, 7.33; N, 3.64.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=[O:4].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Yield: 85.2 %

Procedure:
(3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (7.0 g, 21.0 mmol) were dissolved in methanol (60 mL) and treated with NaOMe (30% in methanol, 0.9 mL, 4.50 mmol) for 24 h at ambient temperature. The volatiles were removed and the residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 9:1) to yield the title compound (5.9 g, 84%) as a colorless oil. ES-MS m/e: 330.8 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:24]1(B(O)O)[CH2:26][CH2:25]1>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]1([C:2]2[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[N:6]=2)[CH2:26][CH2:25]1
Reactant: OB(O)C1CC1
Reactant: Cn1cc(C(=O)OCc2ccccc2)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C(=O)OCc2ccccc2)nc1C1CC1
Temperature: 100 °C

Procedure:
Into a solution of benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (2.8 g, 9.49 mmol) in THF (40 ml) and water (20 ml), cesium carbonate (7.71 g, 23.7 mmol) and cyclopropyl boronic acid (1.22 g, 14.2 mmol) were added under argon atmosphere at RT. The resulting mixture was degassed and purged with argon for 10 min. Pd(PPh3)2Cl2 (0.332 g, 0.04 mmol) was added to the mixture and heated at 100° C. for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography. Yield 1.1 g. 1H-NMR (400 MHz; CDCl3): δ 0.95-1.02 (m, 2H), 1.07-1.11 (m, 2H), 1.72-1.78 (m, 1H), 3.70 (s, 3H), 5.32 (s, 2H), 7.29 (s, 1H), 7.42-7.62 (m, 5H), LC-MS: [M+1]=257.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.[C:12]([Cl:15])(Cl)=[O:13]>C1C=CC=CC=1>[CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.[C:12]([Cl:15])(=[O:13])[NH2:2]
Reactant: O=C(Cl)Cl
Agent: C1=CC2(CCC1)CCCNC2
Solvent: c1ccccc1
Product: NC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-azaspiro-[5.5]-undec-7-ene (13 g.; 0.086 mole) in benzene (25 ml.) is added dropwise, under ice cooling, to a solution of phosgene (9 g.; 0.09 mole) in benzene (100 ml.). The solution is stirred at room temperature for 1 hour and concentrated under reduced pressure. Distillation of the residual colorless liquid affords 7.5 g. (41% yield) of 2-azaspiro-[5.5]-undec-7-enecarbamoyl chloride, b.p. 110°-113° C./0.50 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(N)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccnc(/C=C\c2cccc(N)c2)c1
Reaction time: 20 h
Yield: 36.7 %

Procedure:
To a mixture of tert-butyl {2-[(3-aminophenyl)ethynyl]pyridin-4-yl}carbamate (430 mg, 1.4 mmol) in methanol (15 mL) was added 10% palladium on carbon (150 mg, 0.14 mmol) and hydrogenated at 60 psi for 20 hours. After filtration and concentration, the crude residue was purified by silica gel column chromatography to give the desired product (160 mg, 37%). LCMS for C18H22N3O2 (M+H)+: m/z=312.1
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[NH2:38])[CH2:31][CH2:30][CH2:29]1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[NH:28][CH2:29][CH2:30][CH2:31]3)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: Nc1cccc2c1NCCC2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(Nc1cccc2c1NCCC2)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 1,2,3,4-tetrahydro-quinolin-8-ylamine (commercially available; CAS RN 54012-92-9) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (88%). MS (ESI): m/z=414.077 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]2)=[O:8].[OH:25]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]2)(=[O:25])=[O:8]
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCS(=O)c3ccccn3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)(=O)c3ccccn3)ccc2[nH]1

Procedure:
Prepared analogous to Example 124 from 6-[4-(2-pyridylsulfinyl)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1

Procedure:
The first step was to protect 6-aminocaproic acid using benzyl chloroformate to give N-benzyloxycarbonyl-6-aminocaproic acid. This first step was carried out as follows. A solution of 6-aminocaproic acid (32.8 g, 0.25M) in 75 mL of H2O and 42 mL of 6N NaOH was cooled in a salt-ice bath to below 10° C. With stirring, benzyl chloroformate, 46.9 g, 0.275M) and 2N NaOH (138 mL) were alternatively added in small portions over 90 min. After the addition was complete, the solution was brought to room temperature, and stirring was continued for an additional 1 hr. The product was precipitated by lowering the pH to 2 with concentrated HCL, and H2O was added as required to keep the suspension stirring. The white precipitate was filtered, then resuspended and triturated with 1 liter of water. The solid was filtered, washed with water, compressed and then washed with hexane. The solid was then thoroughly dried in a vacuum desiccator to yield 55 grams (83% yield) of N-benzyloxycarbonyl-6-aminocaproic acid.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1S(O)(=O)=O.[CH3:23][NH:24]C=O.[C-]#N.[Na+].[N+](C1C=CC=CC=1)([O-])=O.C([O-])(=O)C.[Na+]>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1[C:23]#[N:24]
Reactant: CNC=O
Reactant: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: CC(=O)[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: N#Cc1cc(N)c2c(c1N)C(=O)c1ccccc1C2=O
Reaction time: 8 h

Procedure:
A mixture of 174 g of 91.2 percent pure 1,4-diamino-anthraquinone-2-sulphonic acid (as the Na salt), 1,200 ccs of N-methyl-formamide, 63.7 g of sodium cyanide, 62.0 g of nitrobenzene and 41 g of sodium acetate is heated to 80°-85° C., whilst stirring, until, according to the TLC, the starting material has reacted without trace, that is to say for about 8 hours. The reaction mixture is worked up as described in Example 1. After drying, 133 g of a dark blue, crystalline product which, according to analysis, contains 85.5% of 1,4-diamino-2,3-dicyano-anthraquinone and no 1,4-diamino-2-cyanoanthraquinone are obtained. This corresponds to a yield of 78.9% of the pure product.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([S:14](F)(=[O:16])=[O:15])[S:12][CH:13]=2)=[N:6][CH:7]=1.[NH2:23][CH2:24][CH:25]1[CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CC(O)CC>[CH:25]1([CH2:24][NH:23][S:14]([C:11]2[S:12][CH:13]=[C:9]([NH:8][C:5]3[N:4]=[C:3]([NH:18][CH:19]([CH3:22])[CH2:20][OH:21])[C:2]([Br:1])=[CH:7][N:6]=3)[CH:10]=2)(=[O:16])=[O:15])[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: C[C@H](CO)Nc1nc(Nc2csc(S(=O)(=O)F)c2)ncc1Br
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCC(C)O
Product: CC(CO)Nc1nc(Nc2csc(S(=O)(=O)NCC3CC3)c2)ncc1Br

Procedure:
A reaction mixture of 130 mg (0.31 mmol) of (R)-4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonyl fluoride, 22 mg (0.31 mg) of aminomethylcyclopropane, 43 μl (0.31 mmol) of triethylamine as well as 38 mg (0.31 mmol) of DMAP in 2-butanol is stirred under reflux for 43 hours. It is mixed again with 22 mg (0.31 mg) of aminomethylcyclopropane, 43 μl (0.31 mmol) of triethylamine as well as 38 mg (0.31 mmol) of DMAP and stirred for another 24 hours under reflux. After cooling, the batch is purified by chromatography (Flashmaster II, DCM/ethanol 95:5), and the crude product that is obtained is recrystallized (ethanol/diisopropyl ether). 35 mg (0.08 mmol, 26% of theory) of the product 4-[5-bromo-4-(2-hydroxy-1-methyl-ethylamino)-pyrimidin-2-ylamino]-thiophene-2-sulfonic acid cyclopropylmethyl-amide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45](=[N:48][S:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)(=[O:51])=[O:50])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:55]2[CH:54]=[CH:53][C:52]([S:49](=[O:50])(=[O:51])[NH:48][CH:45]([CH3:47])[CH3:46])=[CH:57][CH:56]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: CC(C)=NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NC(C)C)cc2)c1C
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A stirred solution of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.20 g, 0.52 mmol) in dimethoxyethane (10 mL) for 5 minutes at room temperature. Triphenylphosphine (0.031 g, 0.12 mmol), palladium (II) acetate (0.013 g, 0.06 mmol), 4-(N-isopropylylsulfamoyl)phenylboronic acid (0.173 g, 0.71 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford [6-fluoro-4-(4-isopropylsulfamoyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.161 g, 72%) as a solid. MS calcd. for C23H23FNO4S [(M−H)−] 428, obsd. 428.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][N:55]=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][CH:47]1[CH2:51][CH2:50][N:49]([C:56]([NH:55][CH3:54])=[O:57])[CH2:48]1
Reactant: CN=C=O
Reactant: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 59 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-pyrrolidin-3-ylacetamide tris(trifluoroacetate) and methyl isocyanate as starting materials in 59% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.40 (m, 2H), 9.05 (s, 1H), 8.32 (m, 2H), 8.21 (s, 1H), 7.68 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 6.03 (m, 1H), 3.40 (m, 3H), 3.20 (m, 2H), 2.99 (m, 4H), 2.55 (s, 3H), 2.00 (m, 2H), 1.60 (m, 2H). LCMS for C25H28ClN8O2 (M+H)+: m/z=507.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH2:17]I)[N:14]=[C:13]([NH:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][CH3:34]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:16]=[C:15]([CH2:17][N:33]([CH3:34])[CH3:32])[N:14]=[C:13]([NH:19][CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(CI)nc(NC3CCCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)Cc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.1 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-(iodomethyl)-2-pyrimidinamine (160 mg, 0.29 mmol) in tetrahydrofuran (2 mL) was added dimethylamine (730 μL, 2 M in THF, 1.5 mmol) and the reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration provided the crude amine (120 mg, 88%). A portion of the crude amine (26 mg) was purified by flash chromatography (38:2 dichloromethane:methanol to 37:3 dichloromethane-methanol) to provide 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-[(dimethylamino)methyl]-2-pyrimidinamine (15 mg). Rf 0.32 (37:3 dichloromethane:methanol); 1H NMR (CDCl3) δ 8.37 (d, 1H), 7.66 (m, 2H), 7.26 (m, 1H), 7.11 (t, 2H), 7.03 (d, 1H), 6.39 (s, 1H), 5.18 (d, 1H), 4.35 (m, 1H), 3.23 (s, 2H), 2.22 (s, 6H), 2.07 (m, 2H), 1.80–1.45 (m, 6H); MS m/z 465 (M+1); mp 68–75° C.