Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:25]1[CH:34]=[C:33]([CH3:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>CN(C)C=O>[CH3:35][C:33]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[C:25]([O:1][CH:2]([C:7]([O:20][CH3:21])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:34]=1
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1cc(C)c2ccccc2n1)C(OC)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 30.4 %

Procedure:
5.7 g (20 mmol) of Methyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate were dissolved in 90 ml of dimethylformamide, and 0.98 g (22 mmol) of sodium hydride (55% in oil) was added. After stirring for 15 minutes, 3.9 g (22 mmol) of 2-chloro-4-methylquinoline were added. The dark red solution was stirred at room temperature overnight, then cautiously hydrolyzed with 20 ml of water and subsequently extracted with ethyl acetate. The organic phase was washed with water, and dried over magnesium sulfate, and the solvent was removed by distillation. The residue (8.1 g) was then chromatographed on silica gel, resulting in 2.6 g of impure product as oil.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[C:26]1([NH:32][C:33](=[O:34])[S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCSC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a mixture of 15.69 g (54.8 mmol) of octadecanethiol, 250 ml of acetonitrile, and 5 ml (4.9 g, 62 mmol) of pyridine and under a nitrogen atmosphere, 6.52 g (0.54.8 mmol) of phenylisocyanate were added all at once. The mixture was heated to reflux for 2 hours, then cooled to room temperature. The product crystallized, was collected by filtration, and was recrystallized from acetonitrile to give 19.19 g of S-octadecyl phenylcarbamothioate (Compound PS-1), mp 85.5–86.5° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:16]=1)=[O:3].[N+:17](=[CH2:19])=[N-:18]>CCOCC>[N+:17](=[CH:19][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:16]=1)=[O:3])=[N-:18]
Reactant: O=C(Cl)c1ccc2c(c1)sc1ccccc12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccc2c(c1)sc1ccccc12

Procedure:
A solution of 7.9 g. of crude 3-chlorocarbonyldibenzothiophene in 700 ml. of ether was added with stirring to a solution of 2.7 g. of diazomethane in 180 ml. of ether in an ice bath. The solution was stirred for 7 hours and then the solvent was removed, on a steam bath, to yield the crude 3-diazomethylcarbonyldibenzothiophene (7.5 g.) which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].Br[CH2:9][CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: Cn1cnnc1S
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cnnc1SCCCO
Temperature: 40 °C
Yield: 29.4 %

Procedure:
A solution of 4-methyl-4-H-1,2,4-triazole-3-thiol (1.72 g, 15 mmol) and 3-bromopropan-1-ol (1.39 g, 10 mmol) in DMF (10 ml) containing potassium carbonate (1.57 g, 14 mmol) was heated at 40° C. for 30 minutes. The mixture was then partitioned between saturated ammonium chloride and ethyl acetate. The aqueous layer was evaporated to dryness and the residue was triturated with ethyl acetate and methylene chloride. The suspension was filtered and the filtrate was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 3-((4-methyl-4H-1,2,4-triazol-3-yl)sulphanyl)propan-1-ol (510 mg, 30%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.N1C=CN=C1.[CH3:12][C:13]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>C(Cl)Cl.O>[Si:16]([O:6][CH:4]1[CH2:5][NH:2][CH2:3]1)([C:13]([CH3:15])([CH3:14])[CH3:12])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of azetidin-3-ol hydrochloride (5.11 g, 46.7 mmol, 1.0 equiv) and 1H-imidazole (9.52 g, 140 mmol, 3.0 equiv) in DCM (100 mL) at 0° C. was added TBDPSCl (19.18 g, 70 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at rt overnight and then diluted with water, and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was eluted over a silica gel with DCM/MeOH=100/1 to 10/1 to give 12 g of 3-(tert-butyldiphenylsilyloxy) azetidine as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]([C:32](=O)[CH3:33])=[CH:18][C:19]2[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=2)[C:22]([O:24]CCC#N)=[O:23])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([CH:41]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:42][CH2:43][O:44][C:45](=[O:50])/[CH:46]=[C:47](\[NH2:49])/[CH3:48])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC(O)C>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]([C:19]3[CH:31]=[CH:30][CH:29]=[C:21]([C:22]([OH:24])=[O:23])[CH:20]=3)[C:46]([C:45]([O:44][CH2:43][CH2:42][CH:41]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:50])=[C:47]([CH3:48])[NH:49][C:32]=2[CH3:33])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C(N)=C/C(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: CC(=O)C(=Cc1cccc(C(=O)OCCC#N)c1)C(=O)N1CCCN(Cc2ccccc2)CC1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2cccc(C(=O)O)c2)C(C(=O)N2CCCN(Cc3ccccc3)CC2)=C(C)N1

Procedure:
2.05 g (3.99 mmol) of 2-cyanoethyl 3-[2-(4-benzyl-[1,4]diazepane-1-carbonyl)-3-oxobutenyl]benzoate and 1.18 g (3.99 mmol) of (3,3-diphenylpropyl)3-aminocrotonate were stirred in 40 ml of 2-propanol at 80° C. overnight. After the concentration under reduced pressure, the product was purified by the silica gel chromatography (chloroform/methanol=100/1) to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:20]3[CH:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=3)[CH2:15][C@H:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CC[C@@H]3CNC[C@@H]32)cc1
Reactant: Clc1ccc(I)cn1
Product: Clc1ccc(N2C[C@H]3CCN(Cc4ccccc4)[C@H]3C2)cn1
Yield: 65.3 %

Procedure:
cis-1-Benzyloctahydropyrrolo[3,4-b]pyrrole (500 mg, 2.48 mmol), prepared as described in (U.S. Pat. No. 5,071,999), and 2-chloro-5-iodopyridine (643 mg, 2.69 mmol), prepared as described in (Tetrahedron Lett. (1993), 34, 7493-7496), were processed as described in Example 1E to provide the title compound as a tan solid (508 mg, 65% yield). MS (DCI/NH3) m/z 314, 316 (M+H)+.
Reaction SMILES: BrC[C:3]1C=CC=C[C:4]=1[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([CH:17]2[CH2:22][CH2:21][CH:20](C3C=CC=CC=3CBr)[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[C-]#[N:32].[Na+].O1CCOCC1>O>[CH:17]1([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:4][C:3]#[N:32])=[CH:10][CH:11]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [C-]#N
Reactant: O=C(C1CCC(c2ccccc2CBr)CC1)C1CCC(c2ccccc2CBr)CC1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(C(=O)C2CCCCC2)cc1

Procedure:
Crude α-bromo-p-tolylcyclohexyl ketone (17 g.), sodium cyanide (3 g.), dioxan (80 ml.) and water (20 ml.) were heated under reflux for 4 hours. The mixture when cold was poured into water and extracted with ether. Evaporation of the extracts followed by chromatography on silica gave a solid (1.5 g.) which was crystallised from light petroleum (b.p. 60°-80°) m.p. 102°-103°.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH:14][C:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]=1[CH3:21].Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[N:14]([C:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]=1[CH3:21])[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(NC2=C(C)C(=O)CC2)cc1OC1Cc2ccccc2C1
Reactant: ClCc1ccncc1
Agent: Cl
Product: COc1ccc(N(Cc2ccncc2)C2=C(C)C(=O)CC2)cc1OC1Cc2ccccc2C1
Yield: 38.8 %

Procedure:
According to the same procedure as in Example 28, using 3-[3-(2-indanyloxy)-4-methoxyanilino]-2-methyl-2-cyclopenten-1-one produced in Example 10 instead of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one, and using 4-(chloromethyl)pyridine hydrochloride instead of methyl iodide, the title compound (yield 38.8%) was obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.Cl[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:10]=[C:4]2[CH:3]=1
Reactant: O=C(CCl)C(F)(F)F
Reactant: CSc1nc(N)cc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc2nc(C(F)(F)F)cn12
Temperature: 120 °C

Procedure:
5 g (28.5 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine and 6.26 g (42.7 mmol) of 3-chloro-1,1,1-trifluoropropanone are dissolved in 200 ml of DMF and heated at 120° C. for 16 h. After the reaction is complete, water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the product is purified by silica gel chromatography. Drying under high vacuum results in 3.5 g (45% of theory) of the product as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](OCC)=[O:11])=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][OH:11])=[N:2]1
Reactant: CCOC(=O)c1noc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1noc2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
589 mg (3.0 mmol) of ethyl 1.2-benzoisoxazole-3-carboxylate in solution in 10 ml of tetrahydrofuran are added to a suspension of 129 mg (3.5 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction mixture is stirred for one hour at 60° C. and then treated by adding 2 ml of methanol dropwise, filtered through celite and rinsed with ethyl acetate. The organic phases are combined, dried over sodium sulfate and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 heptane/ethyl acetate mixture. 180 mg (39%) of benzoisoxazol-3-ylmethanol are obtained in the form of a white solid.
Reaction SMILES: [CH:1](O)=O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=1)([O-:6])=[O:5].[OH-].[NH4+]>Cl>[CH:12]1[C:7]([N+:4]([O-:6])=[O:5])=[CH:8][C:9]2[NH:14][CH:1]=[N:13][C:10]=2[CH:11]=1
Reactant: O=CO
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2nc[nH]c2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
15 ml of formic acid were added to a suspension of 15.3 g of 4-nitro-1,2-phenylenediamine in 150 ml of 10% hydrochloric acid and the mixture was stirred on a water bath at 80° C. for 3 hours and was cooled. The mixture was made alkaline with concentrated ammonium hydroxide solution and the mixture was filtered. The yellowish needles were washed with water and dried over P2O5 under reduced pressure to obtain 14.3 g (89% yield) of 5(6)-nitro-benzimidazole melting at 209°-211° C.
Reaction SMILES: Cl.[F:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([F:31])[CH:24]=1.[BH4-].[Na+]>CO>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:14][C@H:11]2[CH2:12][CH2:13][N:9]([C:6]3[CH:7]=[N:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:10]2)=[C:25]([F:31])[CH:24]=1
Reactant: NC1CCN(c2ccc(F)nc2)C1
Reactant: O=Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3F)C2)cn1

Procedure:
Dissolve 1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (43 mg, 0.20 mmol) in methanol (1 mL). Add triethylamine (90 μL, 0.65 mmol) and 4-chloro-2-fluorobenzaldehyde (35 mg, 0.22 mmol), vortex and let sit overnight at room temperature. Add sodium borohydride (15 mg, 0.39 mmol) and let sit 1 h. Dilute the mixture with methanol and pour onto a column of Dowex® 50wx4-200 (1.5 g). Wash with methanol and discard the washing, then elute with 5% triethylamine in methanol. Concentrate to give the title compound as a residue. Dissolve the residue in methanol and add 1 N HCl in methanol (0.75 mL). Concentrate and dry in vacuum oven at 50° C. overnight to give the title compound as its hydrochloride salt (53 mg, 74%). 1H NMR (400 MHz, MeOH-d4) δ 7.63 (t, 1H, J=8.0 Hz), 7.58-7.57 (m, 1H), 7.45 (dd, 1H, J=9.6, 2.0 Hz), 7.40 (dd, 1H, J=8.0, 2.0 Hz), 7.36-7.32 (m, 1H), 7.00 (dd, 1H, J=8.8, 2.8 Hz), 4.44 (s, 2H), 4.21-4.15 (m, 1H), 3.74-3.61 (m, 3H), 3.42-3.36 (m, 1H), 2.68-2.60 (m, 1H), 2.38-2.29 (m, 1H), MS (ES): m/z=324 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH2:22][CH:23]1[CH2:25][CH2:24]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)CC2CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)CC2CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+): m/z=364.1, tR (minutes, Method F)=2.52
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[N+:18]([O-:20])=O)([C:3](OCC)=[O:4])=[O:2]>CN(C)C=O.[Pt]>[C:13]([C:12]1[CH:11]=[C:10]2[C:9]([NH:8][C:1](=[O:2])[C:3](=[O:4])[N:18]2[OH:20])=[CH:17][CH:16]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)C(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Yield: 69.9 %

Procedure:
A solution of 4-ethoxalylamino-3-nitrobenzoic acid (14.0 g, 49.6 mmol) in 800 ml of N,N-dimethylformamide was hydrogenated at room temperature and atmospheric pressure in the presence of 1.3 g of 5% platinum on carbon for 2.5 h. The catalyst was filtered off and washed with N,N-dimethylformamide. The filtrate was evaporated to dryness and the residue was triturated with 500 ml of water and filtered. The crude product was dissolved in 900 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4), filtered and reprecipitated with 6 M hydrochloric acid to yield 7.7 g (70%) of the title compound. 1H-NMR (DMSO-d6): 7.25 (d, J=9 Hz, 1H, ArH), 7.75 (dd, J=9 Hz, 2 Hz, 1H, ArH), 7.98 (d, J=2 Hz, 1H, ArH), 12.3 (br.s, 1H, exchangeable).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16](Cl)([Cl:18])=[O:17]>>[Cl:18][C:16]([N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:17]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: O=C(Cl)Cl
Product: O=C(Cl)N1c2ccccc2C=Cc2ccccc21

Procedure:
There is known from the German Patent Specification No. 1,136,707 a process for producing 5H-dibenz[b,f]azepine-5-carboxamide by reaction of 5H-dibenz[b,f]azepine with phosgene to give 5-chlorocarbonyl-5H-dibenz[b,f]azepine and the subsequent reaction thereof with ammonia to obtain the stated compound. The reaction of 5H-dibenz[b,f]azepine with phosgene is performed in toluene firstly at 70° C., and then under reflux. The subsequent reaction of this compound with ammonia is carried out in ethanol at boiling temperature.
Reaction SMILES: C1(C[O:8][C:9](=[O:67])[C@@H:10]([CH3:66])[NH:11][C:12](=[O:65])[C@@H:13]([CH2:40][CH2:41][CH2:42][CH:43]([C:55]([O:57]CC2C=CC=CC=2)=[O:56])[NH:44]C(OCC2C=CC=CC=2)=O)[NH:14][C:15]([O:17][CH:18]([CH3:39])[CH:19]([NH:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:20](=[O:29])[O:21]CC2C=CC=CC=2)=[O:16])C=CC=CC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:55]([CH:43]([NH2:44])[CH2:42][CH2:41][CH2:40][C@H:13]([C:12]([NH:11][C@@H:10]([C:9]([OH:67])=[O:8])[CH3:66])=[O:65])[NH:14][C:15]([O:17][CH:18]([CH3:39])[CH:19]([C:20]([OH:29])=[O:21])[NH:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:16])([OH:57])=[O:56]
Reactant: CCCCCCC(=O)NC(C(=O)OCc1ccccc1)C(C)OC(=O)N[C@H](CCCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCC(=O)NC(C(=O)O)C(C)OC(=O)N[C@H](CCCC(N)C(=O)O)C(=O)N[C@H](C)C(=O)O
Reaction time: 5.5 h

Procedure:
A solution of 1a-1 (140 mg, 0.15 mmol) in EtOAc/EtOH (5 mL:15 mL) is hydrogenated over Pd(OH)2 (Pearlman's catalyst, 20% on C, 100 mg) using a Parr apparatus at an initial pressure of 70 psi. After 5.5 h, filtration and evaporation gives a colorless glass. The latter is triturated with ether and the sides of the flask are scraped to provide a white crystalline powder. The ether solution is removed with a syringe and the solid is washed with two more portions of ether, dried, and characterized as 1a-11: NMR (CD3OD) δ 0.89 (m, 3 H), 1.22 (d, J=6.5, 3 H), 1.24-1.39 (m, 6 H), 1.42 (d, J=7.3, 3 H), 1.45-1.99 (m, 8 H), 2.26 (t, J≈7.5, 2H), 3.62 (m, 1 H), 4.06 (m, 1 H), 4.41 (m, 1 H), 4.89 (br s for OH, NH; one hidden CH signal), 5.14 (m, 1 H); MS (HR-FAB) m/z 519.2671 (M+H calcd. for C22H39N4O10, 519.2666).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][CH:4]([C:6]([N:8]([CH3:10])[CH3:9])=O)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1([F:11])[CH2:5][CH:4]([CH2:6][N:8]([CH3:10])[CH3:9])[CH2:3]1
Reactant: CN(C)C(=O)C1CC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A solution of 3,3-difluoro-N,N-dimethylcyclobutanecarboxamide (24 g, 147 mmol) prepared in Part A in THF (500 mL) was added to a stirred suspension of lithium aluminum hydride (7.5 g, 198 mmol) in 500 mL THF at 0° C. The mixture was allowed to come to RT. After stirring the reaction mixture at RT for 18 h, it was quenched by slowly adding 10 mL 6 N NaOH and 5 mL water at 5° C. with stirring. The mixture was stirred at RT for 0.5 h, dried over Na2SO4 and filtered. The filtrate was concentrated to ca. 30 mL by a careful distillation of most of the THF using a Vigreux column. The remaining material was distilled under slightly reduced pressure (ca. 100-200 mm Hg); the fraction (20 mL, by 70-90° C.) contained the title compound contaminated with THF. The residual THF was carefully purged with a gentle stream of nitrogen to yield 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine (12 g, 80 mmol, 54.7% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.46-2.94 (2H, m), 2.38 (2H, d, J=6.55 Hz), 2.16-2.28 (9H, m).
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:8]=[C:9]2[C:15]([Br:16])=[CH:14][S:13][C:10]2=[CH:11][N:12]=1)(=O)=O.O.[OH-].[Li+]>CS(C)=O>[Br:16][C:15]1[C:9]2[C:10](=[CH:11][N:12]=[C:7]([OH:6])[CH:8]=2)[S:13][CH:14]=1
Reactant: O=S(=O)(Oc1cc2c(Br)csc2cn1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Oc1cc2c(Br)csc2cn1
Temperature: 75 °C
Yield: 100 %

Procedure:
A mixture of 3-bromothieno[2,3-c]pyridin-5-yl trifluoromethanesulfonate (145 mg, 0.400 mmol), lithium hydroxide monohydrate (173 mg, 4.00 mmol) and dimethyl sulfoxide (10 mL) was heated at 75° C. for 2.5 h. The solvent was removed and the residue was neutralized with aqueous 2 N HCl. The residue was then extracted with 30% n-BuOH:EtOAc (3×50 mL). The combined organic extracts were washed with water (2×10 mL) and brine (10 mL), dried over MgSO4, and concentrated in vacuo to afford 92 mg (100%) of the title compound as a yellow solid. MS (ESI): 230.01, 231.97 [M+H]+; HPLC tR=2.46 min (ZQ3: polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH3:21])[CH2:16][CH2:15]2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.B.C1COCC1.Cl.O>C1COCC1>[CH2:20]([N:17]1[CH2:18][CH2:19][N:14]([CH2:12][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=2)[CH2:15][CH2:16]1)[CH3:21]
Reactant: CCN1CCN(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCN(Cc2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (3-amino-5-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (14.6 g, 48.5 mmol) in THF (120 ml) under N2-atmosphere, a 1 M solution of BH3.THF (145.5 ml) is added dropwise (exothermic). The mixture is stirred for 14 h at rt and then 5 h at 65° C. After cooling to rt, HCl conc./H2O 1:1 (250 ml) Is added and the mixture stirred for 15 h. The suspension is filtered, the filtrate extracted 3 times with AcOEt. The organic phases are washed twice with 1 N HCl and then discarded. The combined acidic phases are made basic by addition of saturated Na2CO3 solution and extracted 3 times with AcOEt. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; AcOEt/EtOH/NH3 95:5:1→90:10:1) followed by extraction between 3 portions of AcOEt, 3 portions of water and finally brine, drying (Na2SO4) and concentration yields the title compound as an oil: MS: [M+1]+=288; 1H-NMR (CDCl3): 6.94 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 3.82 (sb, H2N), 3.46 (s, 2H), 2.51 (m, 8H), 2.44 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A mixture of 150 g methyl-4-hydroxybenzoate, 1.5 L 2-butanone, 272.5 g potassium carbonate and 293 ml 1-bromotetradecane is heated at reflux for 66 hours. The reaction is cooled to room temperature, filtered, the filtrate concentrated in vacuo and the residue recrystallized from methylene chloride/hexane to give 258.8 g of the desired product. MP 56°-58° C.