Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C(OC)=CC2C(=O)N(C)CCCC=2C=1.[NH2:17][C:18]1[C:23]2[C:24](=[O:30])[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=[CH:20][C:19]=1[O:31][CH3:32].Cl.COCCO.Cl[C:40]1[N:45]=[C:44]([NH:46][C:47]2[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=2[C:49]([NH:51][CH3:52])=[O:50])[C:43]([Cl:57])=[CH:42][N:41]=1>O1CCOCC1>[Cl:57][C:43]1[C:44]([NH:46][C:47]2[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=2[C:49]([NH:51][CH3:52])=[O:50])=[N:45][C:40]([NH:17][C:18]2[C:23]3[C:24](=[O:30])[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=[CH:20][C:19]=2[O:31][CH3:32])=[N:41][CH:42]=1
Reactant: COc1ccc2c(c1N)C(=O)N(C)CCC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc2c(cc1N)CCCN(C)C2=O
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2C(=O)N(C)CCC3)ncc1Cl
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
7-Amino-8-methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (110 mg, 0.50 mmol) and 9-Amino-8-methoxy-2-methyl-2,3,4,5-tetrahydro-benzo[c]azepin-1-one (prepared following the procedure of 7c) were added as an unseparated mixture with 4 M of Hydrogen chloride in 1,4-Dioxane (300 uL), 2-Methoxyethanol (10 mL, 100 mmol), and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (2 eq) charged into Radley tube. Heat 110° C. for about 3 hours, cooled to room temperature. Solid precipitated out and was filtered. This material was dissolved in dichloromethane/MeOH and treated with 3 eq. of MP-carbonate, stirred 30 min, filtered and concentrated to give 2-[5-Chloro-2-(8-methoxy-2-methyl-1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-9-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as an orange solid (51 mgs, 21%). Melting point: 185-187° C. 1H-NMR (DMSO, 400 MHz): 8.67 (broad m, 1H), 8.67 (s, 1H), 8.47 (broad s, 1H), 8.00 (d, J=7.0 Hz, 1H), 7.47-7.43 (m, 1H), 708-7.03 (m, 2H), 6.82 (d, J=7.8 Hz, 1H), 3.81 (s, 3H), 3.17-3.07 (m, 2H), 2.85 (s, 3H), 2.69-2.65 (m, 2H) 2.50 (s, 3H), 1.78-1.71 (m, 2H); LC/MS: 481.37 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:15]2[C:14](=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:13]([C:24]([N:28]2[CH2:29][CH2:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27]2)=[O:25])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: c1ccc2c(c1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N3CCc4ccccc4C3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
According to the procedure of Yamada et al. (Note 2), a solution of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid (100 mg, 0.3 mmol) and 1,2,3,4-tetrahydro-isoquinoline (44 mg, 0.33 mmol) in 5 mL of THF was stirred at 0° C. under a nitrogen atmosphere. Diethyl cyanophosphonate (54 mg, 0.33 mmol) in 2 mL of THF was added followed by triethylamine (77 μL, 0.55 mmol). The reaction was stirred at 0° C. for 30 minutes and then at room temperature for 15 h. The reaction was diluted with EtOAc and then washed with water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with NH4OH (10% solution in H2O) and then with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The resulting residue was triturated with ether to give 87 mg (66%) of the desired product. H1-NMR (CDCl3): δ 8.30 (s, 1H), 7.27 (broad m, 4H), 6.75 (m, 1H), 6.58 (m, 2H), 5.09 (m, 2H), 4.41 (m, 2H), 3.98 (m, 2H), 3.83 (s, 2H), 3.50 (s, 3H), 3.09 and 2.77 (m, 1H each), 1.52 (s, 9H), [Note: broadening of peaks observed due to Boc group, rotamers also observed.] MS: APCI (M+H) calc'd for C27H31N3O5+H 478.6; found 478.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[F:16][C:17]1[C:25]2[CH:24]=[C:23]([CH2:26]O)[S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:23]2[S:22][C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[C:25]=3[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: OCc1cc2c(F)cccc2s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2cc3c(F)cccc3s2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol), (4-fluoro-benzo[b]thiophen-2-yl)-methanol (0.96 g, 10.5 mmol), and polymer-supported triphenyl phosphine (3.0 g, 10.5 mmol) in THF (35 mL) in an ice-bath was slowly added diisopropyl azodicarboxylate (2.1 mL, 10.5 mmol) and stirred at r.t. overnight. The mixture was filtered and the solid was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (1.5 g, 76% yield). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[NH2:31]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:31][C:30]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:28]([O:27][CH3:26])[CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cc(OC)c(OC)c(OC)c3)nc21
Temperature: 160 °C

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (2.70 mmol) of 3,4,5-trimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. The dark solution was cooled and dissolved in 2 mL of warm glacial acetic acid. This solution was diluted to 15 mL volume with water to precipitate a violet solid. The solid was filtered, washed well with water, and dried; wt 0.140 g. Purification was effected by filtration of an ethyl acetate (30 mL) solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 3 mL volume. The crystals that separated on inducement were filtered and washed with 1 mL of ethyl acetate and 1 mL of ether; wt 0.054 g; mp 275°-278° C.
Reaction SMILES: [OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+]>O1CCOCC1.CCCCC.C(OC(C)C)(C)C>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)ccc2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: CCCCC
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cc(F)ccc4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 46.1 %

Procedure:
A mixture of 0.874 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 8.8 cm3 of dioxane to which had been added 1.37 cm3 of 5N aqueous sodium hydroxide solution was stirred for 17 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. An oil was obtained, which product was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μ; diameter 3 cm; 25 g), elution was carried out with a dichloromethane/methanol (85/15 by volume) mixture, first a fraction of 100 cm3 was collected and then 50-cm3 fractions were collected. Fractions 3 and 4 were combined and concentrated as above. The evaporation residue was taken up in dichloromethane and filtered. The filtrate was concentrated as under the above conditions and then the product obtained was taken up with stirring in 40 cm3 of a pentane/diisopropyl ether (50/50 by volume) mixture for 16 hours at a temperature in the region of 20° C. The crystals obtained were filtered off and washed with 2 times 10 cm3 of the same mixture as above and then 3 times 20 cm3 of pentane. 0.392 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a pale yellow solid melting at 109° C. which was a mixture of two diastereoisomers.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.[ClH:38].O1CCOCC1>CN(C)C=O>[ClH:38].[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[CH2:27][N:11]1[CH2:12][CH2:13][N:8]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:9][CH2:10]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc5ccccc5c4)CC3)cccc2n1
Temperature: 60 °C
Yield: 71 %

Procedure:
In a 20 mL vial with stir bar, triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-(bromomethyl)naphthalene (59 mg; 0.26 mmol) in N,N-dimethylformamide and heated to 60° C. for 72 hours. Mixture was quenched with 1 mL of 1N NaOH and after 1.5 hours solids were collected by filtration and triturated with ethanol. Solids were stirred at room temperature with 4M HCl in Dioxane (2 eq). Solids were collected and dried to 60 mg of title compound. (71% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.7 (s, 1H), 9.38 (s, 1H), 9.07 (s, 1H), 8.16 (s, 1H), 8.00 (m, 3H), 7.85 (dd, J=8.5, 1.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.61 (m, 2H), 7.27 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 4.54 (s, 2H), 3.58 (m, 2H), 3.43 (d, J=11.5 Hz, 2H), 3.32 (t, J=12.0 Hz, 2H), 3.25 (d, J=12.0 Hz, 2H). ESIMS+385.8 m/z
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH2:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-:20])([O-])=[O:18].[Na+].[Na+].[CH3:23][C:24]#[N:25]>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.O>[NH2:25][C@@H:24]([CH2:23][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:10]=[C:11]([NH2:16])[N:12]=2)=[CH:4][CH:3]=1)[C:17]([OH:20])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: CC#N
Reactant: Nc1nc(Cl)cc(SCc2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Nc1nc(SCc2ccccc2)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1

Procedure:
4-(Benzylthio)-6-chloropyrimidin-2-amine (0.1 g, 0.397 mmol), L-p-boronophenylalanine (0.1 g, 0.477 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), Na2CO3 (93 mg, 0.874 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 150° C. for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 0.42 g of the title compound. M+1=381; 1H NMR (CD3OD) δ 7.8 (d, 2H), 7.37 (t, 4H), 7.23 (m, 2H), 7.16 (m, 1H), 6.98 (s, 1H), 4.43 (s, 2H), 4.20 (t, 1H), 3.29 (m, 1H), 3.13 (M, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[OH:28])([CH3:21])[CH3:20])[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36]>>[Cl:36][CH2:35][CH2:34][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]([NH:18][C:14]1[C:13](=[O:29])[N:12]([C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([F:31])[C:9]=2[CH3:30])[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:32])[CH:17]=[CH:16][N:15]=1)([CH3:20])[CH3:21]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Reactant: ClCCBr
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O

Procedure:
The title product was prepared from N-cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 169 g, 0.33 g) and 1-bromo-2-chloroethane using a similar method to that described for example 167e.
Reaction SMILES: [ClH:1].Cl.[C:3]1([CH:9]([CH2:12][NH2:13])[CH2:10][NH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:16]=O>O>[ClH:1].[ClH:1].[C:3]1([CH:9]2[CH2:10][NH:11][CH2:16][NH:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCC(CN)c1ccccc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(C2CNCNC2)cc1
Reaction time: 8 h
Yield: 58 %

Procedure:
37.5 g (0.168 mol) of 2-phenylpropane-1,3-diamine dihydrochloride are dissolved in 100 ml of water, and 13.52 g (0.336 mol) of sodium hydroxide pellets are added. The mixture is cooled in a bath of water+ice and 17 ml of a 30% (w/v) aqueous solution of formaldehyde are added. The mixture is left overnight at room temperature (15°-20° C.) and extracted with 5×50 ml of CHCl3, and the chloroform phase is washed with 25 ml of water, dried over MgSO4 and filtered. The filtrate is evaporated to dryness, the evaporation residue is taken up with 500 ml of anhydrous C2H5OH and acidified with ethanol containing HCl, and the precipitate formed is collected by filtration, washed with a small quantity of anhydrous ethanol and dried in vacuo to give 24 g (yield: 58%) of CRL 41 365. M.p. (inst.)=192° C.
Reaction SMILES: [Na].[O:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9].[H][H]>CO.[Ni]>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: [H][H]
Reactant: O=C(O)C1CCC=CO1
Agent: [Ni]
Agent: [Na]
Solvent: CO
Product: O=C(O)C1CCCCO1

Procedure:
210 g. of the sodium salt of 3,4-dihydro-2H-pyran-2-carboxylic acid (5) wasdissolved in 2 liters methanol and hydrogenated at 3 atm. pressure over 60 g. Raney nickel catalyst. After hydrogen uptake was complete, the catalystwas filtered and the solvents removed in vacuo. The residue was acidified with concentrated hydrochloric acid and extracted with chloroform. Distillation gave 143.8 g. product, b.p. 75° - 80° C./0.4 Mm, n25 = 1.4623.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: CN1CCNCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: CN1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Yield: 43 %

Procedure:
The compound (40 mg, 0.11 mmol) prepared in Example 27 and 1-methylpiperazine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (21 mg, Yield 43%).
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH3:13][C@H:14]([C:27]([OH:29])=[O:28])[C:15]1[CH:16]=[CH:17][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=2[CH:24]=1.[ClH:30].C(OCC)(=O)C.C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH3:13][C@H:14]([C:27]([OH:29])=[O:28])[C:15]1[CH:16]=[CH:17][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=2[CH:24]=1.[ClH:30]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(N)O
Temperature: 25 °C

Procedure:
In 1 ml of dichloromethane, 684 mg (1.76 mmol) of the Boc-aminopropanol-naproxen obtained above was dissolved, and 2 ml of 4 M hydrochloric acid/ethyl acetate was added thereto under ice-cooling, followed by stirring under ice-cooling for 20 minutes and at room temperature for 1 hour. After confirming disappearance of Boc-aminopropanol-naproxen by TLC, and diethyl ether was added thereto, followed by decantation three times. Thereafter, the residue was dried under reduced pressure to quantitatively give the titled substance at a yield of 564 mg. The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>C(O)C.O.[Fe]>[Cl:3][C:4]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Yield: 89.9 %

Procedure:
To a refluxing mixture of iron powder (2.68 g, 48.4 mmol) and ammonium chloride (323 mg, 6.05 mmol) in ethanol (45 mL) and water (8 mL) was added 1-(2,4-dichlorophenoxy)-2-nitrobenzene (AMR01025, 2.5 g, 8.8 mmol) and the resulting mixture was stirred at reflux for 2 h. After removal of the solvent, the residue was diluted in aqueous sodium hydrogen carbonate (40 mL) and extracted with DCM (3×20 mL). The organic layer was dried (MgSO4), filtered and evaporated to give 2-(2,4-dichlorophenoxy)phenylamine (2.01 g, 90%) as a colorless oil which was used in the next step without further purification. Rf: 0.56 (DCM) 1H NMR (400 MHz, CDCl3) δ 3.85 (2H, br s, NH2), 6.75 (1H, m, ArH), 6.84 (1H, d, J=8.8 Hz, ArH), 6.84 (1H, dd, ArH), 6.87 (1H, dd, J=7.6, 1.6 Hz, ArH), 7.04 (1H, m, ArH), 7.17 (1H, dd, J=8.8, 2.4 Hz, ArH) and 7.49 (1H, d, J=2.4 Hz, ArH).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:14](OC(=O)C)(=[O:16])C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(O)=O>[CH:14]([O:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1)=[O:16]
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: c1ccncc1
Product: C=C1CC(OC=O)CCC2=C(C)CCC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
2.67 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene were treated at 0° firstly with half of a mixture of 4.08 g of acetic anhydride, 1.84 g of formic acid and 37 mg of pyridine. The mixture was stirred for 24 hours at room temperature and with exclusion of light. Then the other half of the reagent was added and the mixture stirred for further 24 hours. The solution was poured on to a mixture of ice and sodium carbonate and worked up in a conventional manner. The crude product so obtained (3.18 g) was distilled under high vacuum and yielded 2.70 g (87%) of pure 6-formyloxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.005 50°; IR(film):νmax = 3120, 1728, 1645, 1460/45, 1190/82, 1015/1000, 905/900 cm- 1. The compound smells woody, cedar-like, slightly ionone-like.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH:18]2[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=32)[CH2:3]1.[C:21]([OH:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([OH:31])=[O:30])([C:25]([OH:27])=[O:26])[OH:24]>CC(C)=O.O>[CH3:1][N:2]1[CH2:19][CH:18]2[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=32)[CH2:3]1.[C:21]([O-:33])(=[O:32])[CH2:22][C:23]([CH2:28][C:29]([O-:31])=[O:30])([C:25]([O-:27])=[O:26])[OH:24]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CN1CC2c3ccccc3Oc3ccc(Cl)cc3C2C1
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
150 mg Asenapine free base was dissolved in 3.0 ml acetone and to this solution was added 0.25 ml of a 2M stock solution of citric acid (Fluka #24788) in water. After seeding with a few of crystalline citrate salt according to example 1 a white suspension begins to form after 5 minutes. Stirring was continued at room temperature, and on the next day the suspension was filtered and the product dried under vacuum at room temperature for about 18 hours. The obtained sample was characterized by powder X-ray diffraction, which confirmed that the same crystalline form as in example 1 was obtained. Further investigation by elemental composition analysis showed a composition that is consistent with a 1:1 salt of Asenapine and citric acid as provided in Table 2. Differential scanning calorimetry shows a single melting peak at 174° C. with an enthalpy of fusion of about 116 J/g.
Reaction SMILES: [NH:1]([C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[O:28])[CH:21]=3)=[CH:16][CH:17]=2)[C:12]([Cl:42])=[CH:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:2]1([NH:1][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[C:12]([Cl:42])=[CH:11]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)c(Cl)cn4C(=O)Nc3ccccc3)ccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccc3c(c2)c(Cl)cn3C(=O)Nc2ccccc2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
After dissolving 260 mg of tert-butyl 4-{[(4-{[1-(anilinocarbonyl)-3-chloro-1H-5-indolyl]oxy}-2-pyridyl)amino]carbonyl}-1-piperidinecarboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added, and the mixture was extracted with ethyl acetate and dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 200 mg of N1-phenyl-3-chloro-5-[(2-{[(4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide as a faint yellow solid. After adding 0.5 ml of formaldehyde (37% in water), 170 mg of sodium triacetoxyborohydride, 50 mg of acetic acid and 5 ml of tetrahydrofuran to the solid, the mixture was stirred at room temperature for 10 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added, extraction was performed with ethyl acetate, and the extract was washed once with brine. The obtained ethyl acetate solution was passed through a glass filter coated with NH type silica gel. The silica gel was washed with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 210 mg of a faint yellow oil. The oil was solidified from a hexane and ethyl acetate mixed solvent to obtain 90 mg of a powder.