Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([C@H:17]2[C:30]3[CH:29]=[C:28]4[C:23]([NH:24][C:25](=[O:31])[CH2:26][O:27]4)=[CH:22][C:21]=3[O:20][C:19]([CH3:33])([CH3:32])[C@@H:18]2[OH:34])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][N:9]([C@H:17]2[C:30]3[CH:29]=[C:28]4[C:23]([N:24]([CH3:35])[C:25](=[O:31])[CH2:26][O:27]4)=[CH:22][C:21]=3[O:20][C:19]([CH3:33])([CH3:32])[C@@H:18]2[OH:34])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)[C@H]1c2cc3c(cc2OC(C)(C)[C@@H]1O)NC(=O)CO3
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)COc2cc3c(cc21)OC(C)(C)[C@H](O)[C@H]3N(CCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of t-butyl (2-phenylethyl)(7R*,8S*)-[7-hydroxy-6,6-dimethyl-3-oxo-2,3,4,6,7,8-hexahydro-1,5-dioxa-4-aza-anthracene-8-yl]carbamate (106 mg, 0.23 mmol) in dimethylformamide (2 mL), potassium carbonate (79 mg, 0.57 mmol) and methyl iodide (28 δL, 0.46 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 4 hours. Upon the completion of the reaction, saturated ammonium chloride aqueous solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=2/1) and the aimed product was obtained (yield: 100%).
Reaction SMILES: [C:1]([O-:4])([O-:3])=[O:2].[K+].[K+].O[C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH:11]=[CH:12][CH:13]=1>O1CCCC1>[C:16]([O:2][C:1]([O:4][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])[CH:11]=[CH:12][CH:13]=1)=[O:3])([CH3:18])([CH3:17])[CH3:15]
Reactant: C=C(C)C(=O)Nc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1cccc(OC(=O)OC(C)(C)C)c1

Procedure:
K2CO3 (50 g) is added to a solution of 40.0 g (0.225 mol) of N-(3-hydroxyphenyl)methacrylamide in tetrahydrofuran (THF). A solution of 54.2 g (0.249 mol) of di-tert-butyl pyrocarbonate (di-tert-butyl dicarbonate) in THF is then added dropwise at room temperature while stirring. The reaction is complete after a few hours. The reaction mixture is poured onto ice and extracted with ethyl acetate, the organic phase is dried and the solvent is distilled off. A white crystalline product is obtained which is recrystallized from diisopropyl ether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:13]=[C:12]([C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH:2]=1.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.[CH2:55]([NH:57][CH2:58][CH2:59][C:60]#[N:61])[CH3:56]>CC(N(C)C)=O>[C:60]([CH2:59][CH2:58][N:57]([CH2:55][CH3:56])[C:19]([C:17]1[S:18][C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:13]=2)=[CH:15][CH:16]=1)=[O:21])#[N:61]
Reactant: CCNCCC#N
Reactant: O=C(O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCC#N)C(=O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Yield: 11 %

Procedure:
Combined 5-[2-(Pyridin-3-ylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid (22 mg, 0.065 mmol), DIEA (27 uL, 0.195 mmol), and HATU (36.8 mg, 0.097 mmol) in DMA (0.5 mL) in a Smith microwave vial. Added 3-ethylamino propionitrile (10.9 uL, 0.097 mmol) and heated in microwave for 900 seconds at 90° C. The crude mixture was purified by prep LCMS to afford title compound (2.7 mg, 10.9%). MS: m/z 379 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ1.203 (br t, 3H), 2.88 (br t, J=6.5 Hz, 2H), 3.65 (Br s, 2H), 3.70 (Br s, 2H), 7.33 (dd, J=5, 8.5 Hz, 1H), 7.469 (dd, J=1.5, 6.5 Hz, 1H), 7.497 (dd, J=1.5, 4 Hz, 1H), 7.985 (dd, J=1.5, 4 Hz, 1H), 8.16 (m, 1H), 8.22 (m, 1H), 8.56 (dd, J=1.5, 5 Hz, 1H), 8.95 (d, J=2.5 Hz, 1H), 9.91, (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][PH:10](=[O:12])[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]O>>[C:1]1([CH2:7][CH2:8][CH2:9][PH:10](=[O:11])[O:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[PH](O)CCCc1ccccc1
Reactant: CO
Product: CO[PH](=O)CCCc1ccccc1

Procedure:
Prepared in a similar manner as Reference Example 24 from 3-phenylpropylphosphinic acid and methanol to give a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:19][CH:18]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(I)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Yield: 77.1 %

Procedure:
A mixture of ethoxymethylene malonic acid diethyl ester (20.1 mL, 0.10 mol) and 4-iodoaniline (22 g, 0.10 mole) in toluene (300 ml) was heated to reflux for 1 h. After this period of time, solvents were removed under vacuum, and the crude material was precipitated in methyl tert-butyl ether and the resulting white solid was filtered, and dried under vacuum to give 30 g product.
Reaction SMILES: Cl[C:2]1[C:11](C(C(=CN(C)C)C(OCC)=O)=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6](Cl)=[C:7](F)[CH:8]=2)[N:3]=1.C1([NH2:29])CC1>ClC(Cl)Cl>[CH2:10]1[CH2:11][CH2:2][N:3]2[C:7](=[N:29][CH2:6][CH2:5][CH2:4]2)[CH2:8][CH2:9]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: ClC(Cl)Cl
Product: C1CCC2=NCCCN2CC1
Yield: 122.8 %

Procedure:
A solution of 20.6 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 6 g of cyclopropylamine in 100 cm3 of trichloromethane is stirred at a temperature close to 20° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. The residue is taken up in 180 cm3 of ethanol and 10 g of DBU and the solution obtained is heated at a temperature close to 78° C. for 4 hours. After cooling to a temperature close to 20° C., the precipitate obtained is drained and washed with twice 60 cm3 of ethanol 13.65 g of 8-chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a pale yellow solid melting at 256° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[CH3:17][O:18][C:19]([NH:21][C:22](=NC(OC)=O)OC)=[O:20].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][CH:2]([CH3:16])[CH2:3][N:4]1[C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=[C:22]1[NH:21][C:19](=[O:20])[O:18][CH3:17]
Reactant: CC(C)CNc1c(N)cnc2cccnc12
Reactant: COC(=O)N=C(NC(=O)OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cnc3cccnc3c2n1CC(C)C

Procedure:
A mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine (Gerster et al, U.S. Pat. No. 6,194,425, Example 30 Part A, 4.10 g, 19.0 mmol), 1,3-dimethoxycarbonyl-O-methylisourea (7.21 g, 37.9 mmol), acetic acid (5.69 g, 94.8 mmol), and p-toluenesulfonic acid (3.60 g, 19.0 mmol) in methanol (50 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform (150 mL). The solution was washed sequentially with water (150 mL), aqueous sodium carbonate (150 mL of 4% w/w), water (150 mL), and brine (150 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 1.78 g of methyl [1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate as a white solid, mp 195-197° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:24][CH:25]([F:27])[F:26])=[C:19]([F:28])[CH:18]=2)[CH2:9][CH2:8]1>C1COCC1>[F:28][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][C@H:10]2[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]2)[CH:22]=[C:21]([F:23])[C:20]=1[O:24][CH:25]([F:27])[F:26]
Reactant: Fc1cc(CCCCC2CC[SiH](Cl)CC2)cc(F)c1OC(F)F
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CCCCc2cc(F)c(OC(F)F)c(F)c2)CC1

Procedure:
50 ml (0.13 mols) of a THF solution of 2.5M of propylmagnesium bromide was dropped in a mixed solution of 36.9 g (0.1 mol) of 1-chloro-4-(4-(3,5-difluoro-4-difluoromethoxyphenyl)butyl)-1-silacyclohexane and 300 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments such as removal of solvent and salts, followed by isolation through chromatography to obtain 32.1 g (yield: 85%) of the intended trans isomer product.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28]C=C)[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:33][CH2:34][CH2:35][CH:36]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[C:37]([O:39]CC)=[O:38]>>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH:36]([CH2:35][CH2:34][CH2:33][C:32]([F:31])([F:54])[C:50]([F:51])([F:52])[F:53])[C:37]([OH:39])=[O:38])[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1c2ccc(OCOC)cc2OCC1(CCC)c1ccc(OCOC)cc1
Product: CCCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchroman prepared as in Example 21 and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:31](O)[C@@H:12]2[O:13][Si:14]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:15][Si:16]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:17][CH2:18][C@H:11]2[C:10]1=[CH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:40])CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:31]([F:40])[C@@H:12]2[O:13][Si:14]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:15][Si:16]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:17][CH2:18][C@H:11]2[C:10]1=[CH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](O)[C@H]1OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](F)[C@H]1OCc1ccccc1

Procedure:
To a solution of alcohol 6 (6.5 g, 13.2 mmol) in anhydrous CH2Cl2, (diethylamino)sulfur trifluoride (DAST, 1.84 mL, 13.9 mmol) was added slowly at room temperature. The reaction mixture was quenched with iced H2O after 20 min. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer was then combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was used immediately for the next deprotection step. The analytic sample of 8 was obtained by the purification using column chromatography on a silica gel (EtOAc:Hexanes=1:100 to 1:20).[α]24D −104.08° (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 5.36 (t, J=2.5 Hz, 1H), 5.20 (dd, J=2.5 and 5.0 Hz, 1H), 4.92 (ddd, J=6.0, 7.5 and 55.0 Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.31-4.26 (m, 1H), 4.23-4.16 (m, 1H), 4.01-3.92 (m, 1H), 1.08-0.94 (m, 27H); 13C NMR (100 MHz, CDCl3) δ 142.6 (d, J=9.2 Hz), 137.9, 128.4, 127.8, 127.7, 112.7, 103.4 (d, J=189.0 Hz), 80.4 (d, J=21.3 Hz), 73.8 (d, J=19.8 Hz), 71.3, 61.6, 48.8 (d, J=5.3 Hz), 17.5, 17.4, 17.1, 17.0, 16.9, 16.8, 13.4, 13.3, 12.7, 12.5. HR-MS Calcd. for (C26H43FO4Si2+H)+ 495.2762, found 495.2769.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)#[N:23].[Na+]>>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1)#[N:23]
Reactant: N#Cc1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4ccc(C#N)cc4)cc3c2C1
Yield: 34 %

Procedure:
The product of Example 29, step B and sodium 4-cyanobenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 3:2 hexane/ethyl acetate) provided tert-butyl 8-(4-cyanophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (107 mg, 34%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.09-8.03 (m, 3H), 7.84 (dd, J=5.7, 3.9 Hz, 1H), 7.80-7.76 (m, 2H), 7.55 (d, J=8.4 Hz, 1H), 4.58 (s, 2H), 3.84 (t, J=5.7 Hz, 2H), 2.91-2.82 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.7 %

Procedure:
Commercially available 6-chloro-nicotinic chloride (56.8 mmol, 10 g) was dissolved in 50 ml of anhydrous CH2Cl2 and added dropwise to a solution of diisopropylethylamine (DIEA) (1.2 equivalents, 68.2 mmol, 11.67 ml) and 4-chloroaniline (1.2 equiv., 68.2 mmol, 8.70 g) in 50 ml CH2Cl2 at O° C. The mixture was stirred at room temperature for 20 h, then diluted with CH2Cl2 (200 ml) and washed with water (1×200 ml) and brine (1×100 ml). The organic layer was dried over sodium sulphate and concentrated. The crude was crystallized from diethyl ether to give 13 g of a white solid. Yield=86%. 1H NMR (CDCl3, 200 MHz) δ 7.35 (2H, d, J=8.8 Hz), 7.47 (1H, d, J=8.2 Hz), 7.58 (2H, d, J=8.8 Hz), 7.88 (1H, bs), 8.16 (1H, dd, J=8.4 Hz, J′=2.8 Hz), 8.84 (1H, d, J=2.4 Hz)
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[CH:14]=1)=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[CH:14]=1)=[O:7]
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1F
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1NCCCN1CCOCC1
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-fluorobenzamide was reacted with 3-morpholinopropylamine to give the title compound in 33% yield; m.p. 239-240° C.; NMR Spectrum: (DMSOd6) 1.7 (m, 2H), 2.17 (s, 3H), 2.31 (m, 6H), 2.95 (s, 6H), 3.15 (q, 2H), 3.53 (t, 4H), 6.6 (t, 1H), 6.72 (d, 1H), 6.89 (m, 1H), 7.2 (m, 3H), 7.3 (m, 2H), 7.54 (m, 1H), 7.65 (m, 1H), 7.75 (m, 2H), 9.69 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 516.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>>[N:25]1([CH2:2][C:3]2[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Reactant: c1cn[nH]c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cn2cccn2)cc1

Procedure:
70 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 36 mg of 1H-pyrazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((1H-pyrazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 389.3 (M)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Mg].[CH2:12]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH:19]=[CH:18]1)[CH2:13][CH2:14][CH2:15][CH3:16].Cl>C(OCC)C>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:20]2([OH:23])[CH2:21][CH2:22][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH2:19]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Br)cc1
Reactant: CCCCCC1C=CC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(CCC)cc2)CC1

Procedure:
A solution of 7.1 g of 4-propylbromobenzene in 25 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(4-propylphenyl)-4-hydroxy-1-pentylcyclohexene was obtained as a crude reaction product.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1.Cl[C:33]1[N:38]=[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([CH:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[C:36]([Cl:52])=[CH:35][N:34]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:52][C:36]1[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([CH:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])=[N:38][C:33]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:34][CH:35]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc2CC1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
10-Camphorsulfonic acid (49 mg, 0.21 mmol) was added to 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (44 mg, 0.20 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (66 mg, 0.19 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min). MP-Carbonate (2.69 mmol/g loading; 0.16 g, 0.43 mmol) was added and the mixture stirred for 1 h, then filtered, washing with 2 mL iPrOH. Brine was added, but the only ppt was NaCl. The aq. layer was extracted with EtOAc, and combined with the iPrOH, dried and conc. in vacuo. The residue was taken up in DCM with a few drops of MeOH and chromatographed (ISCO, 2×12 g, 0-10% MeOH:DCM) to afford 5-Chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine as a colorless oil (63 mg, 62%). LCMS 530 (M+H), 1H-NMR (CDCl3): 9.58 (s, 1H), 8.57 (d, 1H, J=8.4 Hz), 8.13 (s, 1H), 7.91 (d, 1H, J=7.9 Hz), 7.59 (dd, 1H, J=7.8, 8.1 Hz), 7.24 (m, 3H), 7.02 (d, 1H, J=7.9 Hz), 6.94 (s, 1H), 3.55 (m, 2H), 3.38 (s, 3H), 3.24 (sept, 1H, J=6.8 Hz), 2.88 (m, 4H), 2.73 (m, 6H), 1.31 (d, 6H, J=6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[OH:8].[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O>>[O:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=[C:12]1[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[NH2:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1cnccc1O
Product: Nc1ccccc1-c1nc2cnccc2o1
Yield: 39.3 %

Procedure:
3-Amino-4-hydroxypyridine (2.225 g, 20.0 mmol) and 2-aminobenzoic acid (2.740 g, 20.0 mmol) were stirred in polyphosphoric acid (40 mL) at 140° C. for 6 hrs. The reaction mixture was poured into distilled water and sodium hydroxide was added until pH=8. The precipitate was collected by filtration and the crude product was purified by chromatography on silica gel eluting with petroleum ether:ethyl acetate:Et3N (160:40:1) to give 2-(oxazolo[4,5-c]pyridin-2-yl)benzenamine (1.659 g, Yield: 39%). 1H NMR (400 MHz, DMSO-d6) δ: 6.68 (1H, t, J=7.6 Hz), 6.93 (1H, d, J=8.0 Hz), 7.17 (2H, s), 7.30 (1H, t, J=7.6 Hz), 7.83 (1H, d, J=5.6 Hz), 7.90 (1H, d, J=8.0 Hz), 8.55 (1H, d, J=5.6 Hz), 9.05 (1H, s); MS (ESI) calcd. for C12H9N3O (m/z): 211, found: 212 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:14](=[O:20])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]3([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:20])[N:13]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)C23CCCC3)cc1OC
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC

Procedure:
Prepared analogous as described for the example B1 (Alternative 1) using 4-(3,4-dimethoxyphenyl)-2,3-diazaspiro[4.4]non-3-en-1-one (compound C10) and tert-butyl 4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B10*HCl)
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:27])[C:4]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:31]>C(Cl)(Cl)Cl>[ClH:31].[ClH:1].[ClH:31].[CH3:27][N:3]([CH3:2])[C:4]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][CH3:14])[CH2:6][CH2:5]1
Reactant: ClC(Cl)Cl
Reactant: CN(CCCN1CCC(c2cccs2)(N(C)C)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNCCCN1CCC(c2cccs2)(N(C)C)CC1
Yield: 98 %

Procedure:
HCl gas was passed through a solution of 1.5 g (1 eq) tert-butyl 3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl(methyl)carbamate in 30 ml chloroform at 0° C. for ˜30 min. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure. After trituration with diethyl ether, 1.5 g (98%) of product were obtained in the form of a white solid.